DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.
Claims 21, 22 and 24-26 are pending and under examination.
35 USC § 101 rejections withdrawn
The rejections of claims 21, 22, 24 and 25 as not being directed to patent eligible subject matter under 35 USC § 101 are withdrawn in view of Applicant’s amendments to claim 21.
35 USC § 112(a) rejections maintained
The rejection of claims 21, 22 and 24-26 for failing to comply with the written description requirement are maintained.
Claim 21 has been amended to recite “treating said subjecting the patient identified at step (c) with a treatment regimen combination of oxaliplatin and a fluoropyrimidine comprising a cumulative dose of oxaliplatin of at least 600 mg/m2.
New claim 26 recites “The method of claim 21, wherein the treatment regimen comprising a combination of oxaliplatin and a fluoropyrimidine comprises oxaliplatin at a cumulative dose of 600 to 800 mg/m2 over a course of six months
However, the specification discloses that “A typical regimen when administering oxaliplatin-based chemotherapy is a cyclic administration (during 1 to 3 days, every two or three weeks), leading to a cumulative dose of about 400 to 500 mg/m2 after 3 months of treatment, or 600 to 800 mg/m2 after 6 months” (page 31, lines 7-10)
The specification also recites “FOLFOX4: 85 mg/m2 oxaliplatin, 400 mg/m2 AF, 400 mg/m2 5-FUb, and 600 mg/m2 5-FUc, administered on day 1, followed by 400 mg/m2AF, 400 mg/m2 5-FUb, 600 mg/ m2 5-FUc administered on day 2 (duration of the cycle: 2 days), cycle to be repeated every two weeks (page 29, line 25-28).
Thus, the limitations “combination of oxaliplatin and a fluoropyrimidine comprising a cumulative dose of oxaliplatin of at least 600 mg/m2” and “combination of oxaliplatin and a fluoropyrimidine comprises oxaliplatin at a cumulative dose of 600 to 800 mg/m2 over a course of six months” are not specifically recited in the specification as originally filed. The claimed therapeutic regimen does not include the frequency of administration, as recited in the specification.
35 USC § 103 rejections maintained
The rejection of claims 21, 22 and 24-26 under 35 U.S.C. 103(a) as being unpatentable over Galon et al (WO 2017/194556, published November 16, 2017, Galon-17, IDS) in view of Galon et al (J Pathology, 232:199-209, 2014, Galon-14) and Grabe et al (US 3013/0330325, published December 12, 2013) in further view of McQuade et al (Curr Med Chem 24:1537-1557, 2017) and De Gramont (US 2008/0085881, published April 10, 2008) are maintained.
Applicant argues that none of the cited documents teaches nor suggests using Immunoscore for adapting specifically oxaliplatin based chemotherapy treatment regimen. Applicant argues that Galon-17 does not disclose or suggest using Immunoscore to adapt specific chemotherapy regimens, particularly doses and/or durations, even less for oxaliplatin (combined with a fluoropyrimidine) specifically. Applicant argues that Galon-17 lacks teaching that Immunoscore allows identifying patients that will benefit from a prolonged period (i.e. a higher cumulative dose) of oxaliplatin based chemotherapy, particularly a chemotherapy comprising oxaliplatin and a fluoropyrimidine. Applicant argues that Galon-17describes that Immunoscore may be a new component of a new version of TNM classification of cancer (the TNM-1), particularly colorectal cancer. It specifies that an international consortium has been initiated to validate and promote the Immunoscore in routine clinical settings. Applicant argues that Galon-17 does not mention specific chemotherapy treatments comprising oxaliplatin (and even less FOLFOX chemotherapy treatment).
In addition, Applicant argues that Grabe but does not disclose or suggest tailoring oxaliplatin dose or duration based on Immunoscore. Applicant argues that Grabe does not teach a correlation between IS scores and a specific oxaliplatin dose regimen. Applicant argue that Grabe also does not describe assessment of the IS based on the percentile values of a reference group for each biomarkers assessed through Immunoscore, and particularly CD3im, CD3ct, CD8im and CD8ct.
Applicant also argues that McQuade does not teach or suggest immunologically guided modulation of oxaliplatin therapy, particularly based on Immunoscore. Applicant argues that De Gramont does not use Immunoscore or immune-based stratification to guide therapy.
Applicant further argues that an ordinarily skilled person in the art would still lack any teaching or rationale to:
• apply Immunoscore prospectively to decide which dose or duration of oxaliplatin in a treatment comprising oxaliplatin and a fluoropyrimidine to apply to a patient, and/or adopt the precise cumulative exposure to oxaliplatin of at least 600 mg/m2 (corresponding to a treatment of about 6 months) in the context of a chemotherapy based on oxaliplatin and a fluoropyrimidine specifically to patients classified as IS Int or High as claimed.
Applicant argues that as described in McQuade, treatment with oxaliplatin, such as with other conventional chemotherapy drugs, induces well-known side effects. Selecting patients for a longer, higher-exposure course therefore represents a clinical trade-off, not a routine parameter optimization. On the other hand, de-escalating dose for patients, particularly patients having poor prognosis, is not obvious at all for clinicians and necessitate strong evidence of non-benefit of higher dose or longer treatment and evolution of clinical guidelines based on this evidence.
Applicant argues that the present application through the examples describes that the benefit of 6-month oxaliplatin-based therapy in patients with IS Int + High was retained in those with clinically high-risk tumors and with clinically low risk tumor, showing that Immunoscore allows refining and improving the existing clinical risk classification. Applicant argues that even if the prior art describes treatment with oxaliplatin at similar dosage of the method of the invention, nothing suggests selecting a specific group of patients based on Immunoscore for treating them with oxaliplatin at this specific dosage depending on their Immunoscore in the context of an oxaliplatin/fluoropyrimidine based chemotherapy.
Applicant’s arguments have been considered but are not persuasive. In response to applicant's arguments against Galon-14, Galon-17, Grabe and McQuade individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Absent unexpected results it would have been obvious to combine Galon-14, Galon-17, Grabe, McQuade and De Gamont to have a method for determining a treatment regimen of a chemotherapeutic agent in a patient affected with a colorectal cancer and treating the patient with the determined treatment regimen comprising quantifying in a tumor sample of the patient based on the density of CD3+ and CD8+ cells in the tumor center and tumor invasive margines, classifying the patient based on an immunscore and subjecting the patient to a treatment regimen comprising oxaliplatin at a cumulative dose of at least 600mg/m2.
Galon-17 discloses methods for classifying patients suffering from a solid cancer, and to methods for assessing the responsiveness of a patient suffering from colorectal cancer to antitumoral treatment by quantifying the densities of CD3 and CD8 in tumor core center and invasive margin regions. Galon-14 disclose that the classification system, Immunoscore, is based on the host response to tumor cells Galon-14 disclose the Immunoscore has been demonstrated to be a prognostic factor superior to the AJCC/UICC TNM classification. McQuade disclose that oxaliplatin is one of the most common therapeutic agents for colorectal cancer. Galon-14 disclose that the classification system, Immunoscore, is based on the host response to tumor cells Galon-14 disclose the Immunoscore has been demonstrated to be a prognostic factor superior to the AJCC/UICC TNM classification. Thus, once colorectal cancer has been diagnosed using densities of CD3 and CD8 in tumor core center and invasive margin regions, it would have been obvious to treat the patient diagnosed as having colorectal cancer with a therapeutic regimen including oxaliplatin. In addition, McQuade discloses combination regimes incorporating irinotecan, a semisynthetic inhibitor of topoisomerase, oxaliplatin, a third-generation platinum compound that causes mitotic arrest via the formation of DNA adducts, and capecitabine, a 5-FU prodrug, are now all established options for use as first-line, second-line and sequential treatment of CRC (Abstract).
In addition, the specification recites that “Densities of CD3 and CD8 are quantified in the center (CT) and invasive margin (IM) of the tumor (CD3ct, CD8ct, CD3im, CD8im) using dedicated Immunoscore Analyzer software. Densities are reported on the pre-defined Percentile scale and mean Percentiles of the 4 markers is calculated to define the Percentile Immunoscore (from 0 to 100). Thus, it appears as if calculating an Immunoscore and classifying a patient as either low, intermediate or high would be dependent on a pre-defined percentile scale.
In response to Applicant’s argument that that none of the cited documents teach nor suggest using Immunoscore for adapting specifically oxaliplatin based chemotherapy treatment regimen, the claims are drawn to a method of treating a patient with either intermediate Immunoscore or high Immunoscore with a combination of oxaliplatin and a fluoropyrimidine. Galon-17 disclose that Immunoscore, was used to quantify densities of CD3 and CD8 will facilitate clinical decision-making including rational stratification of patient treatment (page 1, lines 24-27). Galon-14 introduces the Immunoscore as a prognostic tool for colorectal cancer, superior to TNM staging. Both Grabe (paragraphs 81, 82, 345) and McQuade (Abstract; sections 2.3, 2.3.2, 2.5, 2.5.1; Table 1) disclose the treatment of patients with treating identified colorectal cancer patients with oxaliplatin and a fluoropyrimidine. Thus, once a patient has been diagnosed with colorectal cancer using Immunoscore it would have been obvious to treat the patient with oxaliplatin and a fluoropyrimidine.
In response to Applicant’s argument that selecting patients for a longer, higher-exposure course therefore represents a clinical trade-off, not a routine parameter optimization, it is noted that the specification discloses treatment regimens of 3 months versus 6 months of mFOLFOX6 therapy. FOLFOX6 therapy is a routine therapeutic regimen for colorectal cancer patients. Six months does not appear to be an inordinate amount of time for a therapeutic regimen including oxaliplatin. De Gamont discloses the treatment of colorectal cancer with 85 mg/m2 of oxaliplatin for 12 cycles with a stop and go therapy for at least 24 weeks (paragraphs 57-65). Furthermore, claim 1 neither discloses that the time period for the 600 mg/m2 oxaliplatin was six months nor that the oxaliplatin therapeutic regimen was FOLFOX6 which is a specific therapeutic regimen that includes oxaliplatin and 5-Fu. It appears that the results demonstrate that there was no benefit for the continuation of a FOLFOX6 therapeutic regimen for six months for patients with Low IS.
Applicant states that the Examiner further considers that the specification only discloses efficacy of 3 months versus 6 months of FOLFOX6 therapy according to Immunoscore status and that the claimed methods are not commensurate in scope to the treatment regimen described in the application. Applicant argues that solely to expedite prosecution, and without agreeing with the rejections raised during examination, the claims have been limited to a method for treating a patient suffering from colorectal cancer with a treatment regimen comprising combination of oxaliplatin and a fluoropyrimidine, based selection of specific group of patient and treatment of these patients with specific cumulative dose of oxaliplatin.
In response, as discussed previously, the specification discloses the efficacy of 3 months versus 6 months of mFOLFOX6 therapy according to the Immunoscore® status (page 3, lines 7 to 15). The specification further discloses the beneficial effect of the 6 months- as compared to 3 months- FOLFOX6 regimen was observed in patients with a CD8 CD3 (Int+ High) status (Id). The FOLFOX6 regimen comprises oxaliplatin +5FU + leucovorin (page 26, lines 6-7; page 29, lines 29-31; page 31, lines 22-23). It is noted that FOLFOX6 therapy comprises: 85 mg/m2 oxaliplatin, 400 mg/m2 AF, 400 mg/m2 5-FUb, 2400 mg/m2 5-FUc, administered for 46h (duration of the cycle), cycle to be repeated every 2 weeks. The specification discloses that the FOLFOX6 therapy for a 6 months period with patients with an intermediate or high IS was significantly better than FOLFOX6 therapy for a 6 months period with patients with a Lo IS (Figure 3). The specification discloses that for the FOLFOX6 therapy, median oxaliplatin dose received per patient was 732.39 mg/m2 (mean 8.9 cycles) while in the 3 months period, the median oxaliplatin dose received per patient was 494.22 mg/m2. Thus, the cumulative dose for oxaliplatin averaged 732 mg/m2 over 9 cycles of treatment. Thus, the unexpected results from the claimed method are not commensurate in scope. The claims do not include the number of cycles and length of treatment with the FOLFOX6 therapy nor the doses of leucovorin and 5-FU which would likely be critical factors in the successful therapy for patients with an intermediate or high IS.
McQuade disclose that although proven to be individually effective, multi-agent regimens including leucovorin given in combination or sequentially are now the standard line of chemotherapeutic treatment and are the most promising approaches to curative and non-curative CRC management (section 2.5). Thus, the importance of leucovorin in chemotherapy combinations was known.
Given that FOLFOX therapy was well known for the treatment of colorectal carcinoma, it would have been obvious to examine the efficacy of effect of FOLFOX therapy for 3 to 6 month duration, given that Galon-17 discloses methods for assessing the responsiveness of a patient suffering from colorectal cancer to antitumoral treatment by quantifying the densities of CD3 and CD8 in tumor core center and invasive margin regions, while Graber describes the progression free survival of patients responding to chemotherapy out to 30 months.(Figure 3).
In addition, the specification recites that “Densities of CD3 and CD8 are quantified in the center (CT) and invasive margin (IM) of the tumor (CD3ct, CD8ct, CD3im, CD8im) using dedicated Immunoscore Analyzer software. Densities are reported on the pre-defined Percentile scale and mean Percentiles of the 4 markers is calculated to define the Percentile Immunoscore (from 0 to 100). Thus, it appears that calculating an Immunoscore and classifying a patient as either low, intermediate or high would be dependent on a pre-defined Percentile scale.
Declaration of Dr Galon
3.
Galon notes that none of the aforementioned references, either alone or in combination, teach that lmmunoscore allows identifying patients that will benefit from a higher cumulative dose of oxaliplatin based chemotherapy (at least 600 mg/m2 corresponding to a treatment of about 6 months as presently claimed particularly a chemotherapy comprising oxaliplatin and a fluoropyrimidine. Galon argues that as described in McQuade (§ 2.3.2), treatment with oxaliplatin, and other conventional chemotherapy drugs, induces well-known side effects. Galon argues that selecting patients for a longer, higher-exposure course therefore represents a clinical trade-off, not a routine parameter optimization. Applicant argues that deescalating dose for patients, particularly patients having poor prognosis, is not obvious at all for clinicians and necessitate strong evidence of non-benefit of higher dose or longer treatment and evolution of clinical guidelines based on this evidence.
In response, as discussed above, the specification discloses that the FOLFOX6 therapy for a 6 months period with patients with an intermediate or high IS was significantly better than FOLFOX6 therapy for a 6 months period with patients with a Lo IS (Figure 3). The FOLFOX6 regimen comprises oxaliplatin +5FU + leucovorin (page 26, lines 6-7; page 29, lines 29-31; page 31, lines 22-23). It is noted that FOLFOX6 therapy comprises: 85 mg/m2 oxaliplatin, 400 mg/m2 AF, 400 mg/m2 5-FUb, 2400 mg/m2 5-FUc, administered for 46h (duration of the cycle), cycle to be repeated every 2 weeks. The specification does not discuss any side effect of the FOLFOX6 therapy for the 6 months period versus the 3 months period.
Thus, it appears as if the specification only discloses that lmmunoscore allows identifying patients that would benefit from an extended therapeutic regimen of a 6 months FOLFOX6 therapy instead of a 3 months FOLFOX6 therapy. The specification does not disclose that lmmunoscore allows identifying patients that will benefit from a higher cumulative dose of 600 mg/m2 oxaliplatin. It is noted that claim 1 neither discloses that the time period for the 600 mg/m2 oxaliplatin was six months nor that the oxaliplatin therapeutic regimen was FOLFOX6 which is a specific therapeutic regimen that includes oxaliplatin and 5-Fu. There is no evidence that different therapeutic regimens with different individual dosages and dosing frequency would have achieved the same results.
Furthermore, it appears that calculating an Immunoscore and classifying a patient as either low, intermediate or high would be dependent on a pre-defined Percentile scale.
In response to Applicant’s argument that selecting patients for a longer, higher-exposure course therefore represents a clinical trade-off, not a routine parameter optimization, there is no evidence in the specification that side effects were a concern for a longer FLOFOX6 therapeutic regimen.
4.
Galon argues that a person of ordinary skill in the art would not have applied a longer duration of treatment based on an Intermediate or High Immunoscore who is considered as having a good prognosis based on the prior art. Galon argues that a skilled person would have rather expected that patients with IS Low, who were shown to have the highest risk of recurrence and/ or death, would be the ones who benefit most from the 6-month combination regimen compared with those with the 3- month therapy. The present inventors have shown that this is not the case. Applicant argues that as shown in the examples and especially in Figure 3 of the present application, no benefit from the 6-month therapy was shown in patients with IS Low. Only patients with IS Int or High gained from 6 months of combination treatment as compared with 3 months of therapy. Applicant states that both clinically low risk and high-risk patients with IS Int or High had a significantly prolonged DFS with the 6-month regimen compared to the 3-month regimen (see figure 3B and 3C), Applicant argues that even low-risk patients could effectively benefit from 6 months treatment, depending on the IS status.
In response, as discussed above, specification discloses that the FOLFOX6 therapy for a 6 months period with patients with an intermediate or high IS was significantly better than FOLFOX6 therapy for a 6 months period with patients with a Lo IS (Figure 3). It is not clear why a person of ordinary skill in the art would not have applied a longer duration of treatment to colorectal cancer patients regardless of ID status. FOLFOX6 therapy is a routine therapeutic regimen for colorectal cancer patients. Six months does not appear to be an inordinate amount of time for a therapeutic regimen. De Gamont discloses the treatment of colorectal cancer with 85 mg/m2 of oxaliplatin for 12 cycles with a stop and go therapy for at least 24 weeks (paragraphs 57-65).
Furthermore, as described above, claim 1 neither discloses that the time period for the 600 mg/m2 oxaliplatin was six months nor that the oxaliplatin therapeutic regimen was FOLFOX6 which is a specific therapeutic regimen that includes oxaliplatin and 5-Fu.
In response to Applicant’s argument that Galon argues that a skilled person would have rather expected that patients with IS Low, who were shown to have the highest risk of recurrence and/ or death, would be the ones who benefit most from the 6-month combination regimen compared with those with the 3- month therapy, it is not clear why one of skill in the art would have expected patients with IS Low benefit most from the 6-month combination regimen. This is a patient population with a greater risk of recurrence or death. It would be surprising that patients with IS Low would have the same benefit as patients with IS High from the 6-month combination regimen given that they appear to have a weakened immune response to the tumor.
5.
Galon argues that the advantage of a longer duration of treatment only observed in IS patients (Int+ High) was counter-intuitive before the invention. Galon argues that this is well described in the scientific publication submitted herewith relating the results obtained and described in Pages et al. Galon argues that the prior art provides no reasonable expectation that IS would accurately identify the specific subgroup of High and Intermediate IS for whom the benefit of high dose oxaliplatin outweighs the added toxicity, independently of their clinical risk, while the patients identified as Low IS do not have any benefit when receiving a high dose oxaliplatin treatment.
In response, as discussed above, the specification discloses that the FOLFOX6 therapy for a 6 months period with patients with an intermediate or high IS High was significantly better than FOLFOX6 therapy for a 6 months period with patients with a Lo IS (Figure 3). FOLFOX6 therapy is a routine therapeutic regimen for colorectal cancer patients. Six months does not appear to be an inordinate amount of time for a therapeutic regimen including oxaliplatin. De Gamont discloses the treatment of colorectal cancer with 85 mg/m2 of oxaliplatin for 12 cycles with a stop and go therapy for at least 24 weeks (paragraphs 57-65).
Furthermore, as described above, claim 1 neither discloses that the time period for the 600 mg/m2 oxaliplatin was six months nor that the oxaliplatin therapeutic regimen was FOLFOX6 which is a specific therapeutic regimen that includes oxaliplatin and 5-Fu. It appears that the results demonstrate that there was no benefit for the continuation of a FOLFOX6 therapeutic regimen for six months for patients with Low IS.
6.
Galon states that combination of oxaliplatin with other chemotherapy drugs is well known in the art. It is a common strategy in cancer treatment, especially for colorectal cancer, because it improves the effectiveness of therapy through synergistic effects. Galon states that the examples are based on a FOLFOX therapy which corresponds to the combination of oxaliplatin, 5-fluorouracil and leucovorin. Applicant argues that, as explained above, the advantage of assessing lmmunoscore in patients is linked to the role of chemotherapy on immune response. Applicant argues that a skilled person in the art would specifically adapt the dose of oxaliplatin in the context of a treatment based on oxaliplatin and 5-fluorouracil, more particularly FOLFOX therapy, when assessing the prediction of response or therapy efficacy based on Immunoscore, which specifically assesses the immune response against the tumor at the tumor site. Applicant argues that while the dosage of the other drugs potentially used in combination with oxaliplatin may also be adapted by the clinicians taking into account all parameters, the contribution of the invention is linked to the modulation of the dose of the drug inducing immune cell death.
In response, as described above, claim 1 neither discloses that the time period for the 600 mg/m2 oxaliplatin was six months nor that the oxaliplatin therapeutic regimen was FOLFOX6 which is a specific therapeutic regimen that includes oxaliplatin and 5-Fu. There is no evidence that oxaliplatin and 5-Fu with different timing and dosages compared to the therapeutic regimen of FOLFOX6 would have had the same results. It is not clear that a skilled person in the art would specifically adapt the dose of oxaliplatin in the context of a treatment based on oxaliplatin and 5-fluorouracil when assessing the prediction of response or therapy efficacy based on Immunoscore given that only one therapeutic regimen, the FOLFOX6 therapeutic regimen was used in the study and that FOLFOX6 was a routine therapeutic regimen for the treatment of colorectal cancer.
It appears that the results demonstrate that there was no benefit for the continuation of a FOLFOX6 therapeutic regimen for six months for patients with Low IS. It is not clear whether the results from the therapeutic regimen of FOLFOX6 for 6 months for patients with a high IS compared to the therapeutic regimen of FOLFOX6 for 3 months for patients with a high IS was unexpected. But as stated previously, the claims do not specifically recite the FOLFOX6 therapeutic regimen.
NEW REJECTIONS:
Claim Rejections - 35 USC § 112
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 21, 22 and 24-26 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 (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 21 recites “(b) classifying the patient in a group based on an Immunoscore (IS) determined by the densities of CD3ct, CD8ct, CD3im, and CD8im quantified in step (a); wherein: (i) a Low IS group corresponds to a mean percentile below 25%, (ii) an Intermediate IS group corresponds to a mean percentile between 25% and 70%, and
(iii) a high IS group corresponds to a mean percentile above 70%; and (c) identifying the patient as classified to the Intermediate IS group or the high IS group based on the classification of step (b),”. The specification recites that “Densities of CD3 and CD8 are quantified in the center (CT) and invasive margin (IM) of the tumor (CD3ct, CD8ct, CD3im, CD8im) using dedicated Immunoscore Analyzer software. Densities are reported on the pre-defined Percentile scale and mean Percentiles of the 4 markers is calculated to define the Percentile Immunoscore (from 0 to 100). Thus, it appears that calculating an Immunoscore and classifying a patient as either low, intermediate or high would be dependent on utilizing a pre-defined Percentile scale. It is not clear whether an Immunoscore depends only on the cumulative staining density of CD3ct, CD8ct, CD3im, CD8im.
Furthermore, it appears that the term “immunoscore” is defined differently by different groups. Lu et al (US 2005/0032099, published February 10, 2005). disclose Immunoscore as the mean of two scores for separately assessed samples analyzed semi-quantitatively by light microscopy equipped with MetaMorph imaging software (paragraphs 28, 29, 71, 76; Fig 8). Hsu et al (J Pathol 12(e7007):1-5, 2026) discloses that original Immunoscore was a simple binary classification (high or low) of the CD3+ and CD8+ T-cell densities in the tumour core (TC) and invasive margin (IM), using predefined cut-offs, further stratified into a total score of 0–4 based on the summation of the number of ‘high’ categories in the 4 cell/regions (page 1, 2nd column, 2nd paragraph).
progressively evolved into the current commercial version (HalioDx/Veracyte) requiring a dedicated proprietary module integrated with digital pathology software (page 1, 2nd column, 2nd paragraph to page 2, 1st column, 1st paragraph). Thus, it appears that (b) classifying the patient in a group based on an Immunoscore determined
by the densities of CD3ct, CDSct, CD3im, and CDSim may be achieved using various methods including a method using a dedicated proprietary module integrated with digital pathology software. Thus, one of ordinary skill in the art would not be able to know how to classify a patient in a group based on an Immunoscore (IS) determined by the densities of CD3ct, CD8ct, CD3im, and CD8im without first knowing the pre-defined percentile scale or possibly whether a dedicated proprietary module integrated with digital pathology software was used to determine the IS.
Summary
Claims 21, 22 and 24-26 stand rejected
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/MARK HALVORSON/Primary Examiner, Art Unit 1646