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 .
Claims 1-22 are pending and currently under consideration.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-18 rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for methods of predicting success of anti-PD-L1 blockade treatment of urothelial carcinoma (UC) wherein high PD-L1 expression, high TMB, lack of FGFR3 somatic mutations, and/or presence of a somatic mutation in at least one of ARID1A or NOTCH1 gene predicts success of the treatment, does not reasonably provide enablement for methods of predicting success of just any type of treatment of urothelial carcinoma (UC) wherein high PD-L1 expression, high TMB, lack of FGFR3 somatic mutations, and/or presence of a somatic mutation in at least one of ARID1A or NOTCH1 gene predicts success of the treatment. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to perform the invention commensurate in scope with these claims.
Factors to be considered in determining whether undue experimentation is required are summarized in Ex parte Forman, 230 USPQ 546 (BPAI 1986). They include the nature of the invention, the state of the prior art, the relative skill of those in the art, the amount of direction or guidance disclosed in the specification, the presence or absence of working examples, the predictability or unpredictability of the art, the breadth of the claims, and the quantity of experimentation which would be required in order to practice the invention as claimed.
The instant claims are broadly drawn to methods of predicting success of just any type of treatment of urothelial carcinoma (UC) wherein high PD-L1 expression, high TMB, lack of FGFR3 somatic mutations, and/or presence of a somatic mutation in at least one of ARID1A or NOTCH1 gene predicts success of the treatment. This includes predicting success of a treatment based on a marker that has yet to be shown to correlate with success of the treatment.
This invention is in a class of invention which the CAFC has characterized as "the unpredictable arts such as chemistry and biology". Mycogen Plant Sci., Inc. v. Monsanto Co., 243 F.3d 1316, 1330 (Fed. Cir. 2001).
The specification discloses, and the prior art renders obvious (see rejections below), methods of predicting success of anti-PD-L1 blockade treatment of urothelial carcinoma (UC) wherein high PD-L1 expression, high TMB, lack of FGFR3 somatic mutations, and/or presence of a somatic mutation in at least one of ARID1A or NOTCH1 gene predicts success of the treatment. However, the specification and the prior art do not teach high PD-L1 expression, high TMB, lack of FGFR3 somatic mutations, and/or presence of a somatic mutation in at least one of ARID1A or NOTCH1 gene correlate with success of just any UC treatment.
The level of unpredictability for using a particular expression pattern of a particular marker to detect any disease state (such as a disease state susceptible to a particular therapeutic) is quite high. The state of the prior art dictates that one of skill in the art would not predict that a particular marker is indicative of a particular diseased state without a demonstration that said particular diseased stated correlates with said particular marker. For example, Tockman et al (Cancer Res., 1992, 52:2711s-2718s) teach considerations necessary in bringing a cancer biomarker (intermediate end point marker) to successful application. Absent evidence demonstrating a particular marker correlating with a particular diseased state, one of skill in the art would not predict said particular marker correlates with said particular diseased state without undue experimentation. Experimentation to identify such a correlation would in itself be inventive.
One cannot extrapolate the teachings of the specification to the scope of the claims because the claims are broadly drawn to methods of predicting success of just any type of treatment of urothelial carcinoma (UC) wherein high PD-L1 expression, high TMB, lack of FGFR3 somatic mutations, and/or presence of a somatic mutation in at least one of ARID1A or NOTCH1 gene predicts success of the treatment, and Applicant has not enabled said method because it has not been shown that high PD-L1 expression, high TMB, lack of FGFR3 somatic mutations, and presence of a somatic mutation in at least one of ARID1A or NOTCH1 gene are indicative of a UC that is responsive to just any therapeutic treatment. Further, undue experimentation would be required to determine which treatments encompassed by the claims would, or would not, be successful in UC patients exhibiting high PD-L1 expression, high TMB, lack of FGFR3 somatic mutations, and/or presence of a somatic mutation in at least one of ARID1A or NOTCH1 gene in order to perform the method as broadly claimed with any expectation of success.
In view of the teachings above and the lack of guidance, workable examples and or exemplification in the specification, it would require undue experimentation by one of skill in the art to determine with any predictability, that the method would function as claimed.
Claim Rejections - 35 USC § 102
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.
Claim(s) 1, 3-5, and 8 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Massard et al (Annals of Oncology, 2019, 50(Supp 5): v508).
Massard et al teaches a method of predicting success of a UC durvalumab treatment in a patient comprising determining the expression of PD-L1 on the patient’s tumor cells and immune cells, and determining the patient’s TMB, wherein high PD-L1 expression (≥25% of tumor cells or immune cells) and high TMB predict success of the treatment with an increase in survival as compared to UC patents from two studies (see entire Abstract).
Claim Rejections - 35 USC § 102
Claim(s) 9, 10, and 19 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Roghmann et al (Annals of Oncology, 2019, 30(Supp 5): v375-v376).
Roghmann et al teaches detecting the presence or absence of FGFR3 mutations or gene fusions in UC tumor samples from patients treated with anti-PD-L1 inhibitors and that UC patients with FGFR3 alterations had inferior disease specific survival than UC patients without FGFR3 alterations (see Results, in particular). As defined by claims 9-10, said method predicts success of UC treatment with durvalumab.
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.
Claims 1, 3-6, and 8 are rejected under 35 U.S.C. 103(a) as being unpatentable over Zhu et al (Journal for Immunotherapy of Cancer, 2018, 6(4):1-10).
Zhu et al teaches PD-L1 positivity in tumor cells and immune cells of patients with urothelial carcinoma (UC) correlates with anti-PD-L1 blockade therapy, including durvalumab therapy, success (page 2 and Table 1, in particular). Zhu et al teaches defining such PD-L1 positivity as PD-L1 expression by ≥25% tumor cells or immune cells in a study that previously treated the UC patients with platinum chemotherapy (Ref [7] of Table 1, in particular). Zhu et al further teaches metastatic UC patients in the highest quartile of tumor mutational burden (TMB) had a significantly longer median OS when treated with atezolizumab anti-PD-L1 blockade therapy compared to those in lower quartiles (left column on page 6, in particular).
Zhu et al does not specifically teach determining both expression of PD-L1 and TMB in a single patient with UC. However, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to predict whether a patient with UT will therapeutically respond to an anti-PD-L1 therapy of Zhu et al comprising (i) determining the expression of PD-L1 on the patient’s tumor cells and immune cells and use just any cut-off of Zhu et al (such as PD-L1 expression by ≥25% tumor cells or immune cells) to characterize PD-L1 positivity and (ii) determine the patient’s TMB wherein high PD-L1 expression and high TMB predicts successful treatment with the anti-PD-L1 therapy because Zhu et al teaches both PD-L1 positivity and high TMB as indicators of success to anti-PD-L1 therapy. This is an example of both (i) some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference to arrive at the claimed invention and (ii) combining prior art elements according to known methods to yield predictable results. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Claim Rejections - 35 USC § 103
Claim(s) 1-6, 8-12, 19, and 20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Zhu et al (Journal for Immunotherapy of Cancer, 2018, 6(4):1-10) as applied to claims 1, 3-6, and 8 above, and further in view of Roghmann et al (Annals of Oncology, 2019, 30(Supp 5): v375-v376).
Teachings of Zhu et al are discussed above.
Zhu et al does not specifically teach detecting FGFR3 mutations in UC tumor samples. However, these deficiencies are made up in the teachings of Roghmann et al.
Roghmann et al teaches detecting the presence or absence of FGFR3 mutations or gene fusions in UC tumor samples from patients treated with anti-PD-L1 inhibitors and that UC patients with FGFR3 alterations had inferior disease specific survival than UC patients without FGFR3 alterations (see Results, in particular).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the method of predicting whether a patient with UT will therapeutically respond to an anti-PD-L1 therapy rendered obvious by Zhu et al wherein the presence or absence of FGFR3 mutations is determined in a UT tumor sample from the patient because PD-L1 positivity, high TMB, and absence of FGFR3 alterations are all indicators of success to anti-PD-L1 therapy. This is an example of combining prior art elements according to known methods to yield predictable results. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Claim Rejections - 35 USC § 103
Claim(s) 1-13, 19, and 20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Zhu et al (Journal for Immunotherapy of Cancer, 2018, 6(4):1-10) in view of Roghmann et al (Annals of Oncology, 2019, 30(Supp 5): v375-v376) as applied to claims 1-6, 8-12, 19, and 20 above, and further in view of Wang et al (European Urology, 2019, 599-603) and Hayashi et al (Cancer Science, 2019, 110: 1771-1779).
Teachings of Zhu et al and Roghmann et al are discussed above.
Zhu et al and Roghmann et al do not specifically teach using cell-free tumor DNA (ctDNA) to determine if a patient has a somatic mutation in FGFR3. However, these deficiencies are made up in the teachings of Wang et al and Hayashi et al.
Wang et al identifies the S249C FGFR3 mutation as a common FGFR3 mutation indicative of non-responsiveness to anti-PD-L1 inhibitor (Figure 1, in particular).
Hayashi et al teaches using cell-free tumor DNA (ctDNA) to determine if a patient has the S249C somatic mutation in FGFR3, wherein the mutation was commonly found in UC patients (page 1772 and Table 1, in particular).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the combined method of Zhu et al and Roghmann et al that determines whether a UC patient is responsive to anti-PD-L1 therapy based on the absence of FGFR3 indicative of a responsive patient wherein ctCDNA of Hayashi et al is used to determine presence or absence of S249C somatic mutation in FGFR3 because Wang et al identifies the S249C FGFR3 mutation as a common FGFR3 mutation indicative of non-responsiveness to anti-PD-L1 inhibitor and Hayashi et al teaches ctDNA as a non-invasive source to determine whether or not FGFR3 has a mutation that is commonly found in UC patients. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Claim Rejections - 35 USC § 103
Claims 14-16, 18, 21, and 22 are rejected under 35 U.S.C. 103(a) as being unpatentable over Kuziora et al (Annals of Oncology, 2018, 29 (Supplement 10)20).
Kuziora et al teaches UC patients with mutations in ARID1A and NOTCH1 genes detected in circulating tumor DNA (ctDNA) predictably respond to anti-PD-L1 durvalumab therapy (see Results, in particular).
Kuziora et al does not specifically describe the mutations as “somatic” mutations. However, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to predict success of anti-PD-L1 durvalumab therapy with urothelial carcinoma (UC) patients and therapeutically treat the patients comprising determining whether the patient has ctDNA with just any type of mutations (genomic or somatic) in ARID1A and NOTCH1 genes wherein presence of the mutations predict increased overall response to anti-PD-L1 durvalumab therapy and administer anti-PD-L1 durvalumab therapy to patients predicted to have increased overall response to anti-PD-L1 durvalumab therapy because Kuziora et al teaches UC patients with mutations in ARID1A and NOTCH1 genes detected in circulating tumor DNA (ctDNA) predictably respond to anti-PD-L1 durvalumab therapy (see Results, in particular). Further, due to an increase in overall response, the responding patients predictably have an increase in overall survival as compared to some type of standard of care. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Claim Rejections - 35 USC § 103
Claim(s) 14-18, 21, and 22 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kuziora et al (Annals of Oncology, 2018, 29 (Supplement 10)20) as applied to claims 14-16, 18, 21, and 22 above, and further in view of Liu et al (Urothelial Carcinoma, 2015, 33 (7 Suppl) Abstract 300).
Teachings of Kuziora et al are discussed above.
Kuziora et al does not specifically teach patients have previously received a platinum-based chemotherapy. However, these deficiencies are made up in the teachings of Liu et al.
Liu et al teaches post-cystectomy cancer specific survival of urothelial cancer patients who fail to respond to cisplatin-based neoadjuvant chemotherapy is poor and suggests exploring other therapies for urothelial cancer patients who fail to respond to cisplatin-based neoadjuvant chemotherapy (Background, in particular).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the method rendered obvious by Kuziora et al with UC patients of Liu et al who have failed cisplatin-based neoadjuvant chemotherapy because anti-PD-L1 durvalumab is a therapy for UC patients and Liu et al teaches exploring other therapies for urothelial cancer patients who fail to respond to cisplatin-based neoadjuvant chemotherapy. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
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 1-18 are rejected under 35 U.S.C. 101 because the claimed invention is directed to judicial exception(s) (i.e., a law of nature, a natural phenomenon, and/or an abstract idea) without significantly more. The rationale for this determination is explained below:
Claims 1-18 are directed to natural phenomenon because the claims recite natural phenomenon (“Step 2A prong one”) and the judicial exception(s) is/are not integrated into a practical application (“Step 2A prong two”). The “natural phenomenon” include: PD-L1 expression, TMB, mutation status of FGFR3, mutation status of ARID1A, and mutation status of NOTCH1 correlate with response to treatment. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception(s). A claim that focuses on judicial exception(s) can be shown to recite something “significantly more” than the judicial exception(s) by reciting a meaningful limitation beyond the judicial exceptions. However, in the instant case, the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the additional elements (when considered both individually and as an ordered combination) are limited to well-understood, routine and conventional limitations of detecting PD-L1 expression, detecting TMB, and/or detecting the presence or absence of gene mutations using well-understood, routine, and conventional techniques (“Step 2B”). Well-understood, routine and conventional limitations are not meaningful limitations and are not enough to qualify the claimed method as reciting something “significantly more” than the judicial exception(s) (see Part I.B.1 of the interim Guidance).
MPEP 2106.05(d)(II) provides a non-limiting list of laboratory techniques recognized by courts as well-understood, routine, conventional activity. These techniques include:
i. Determining the level of a biomarker in blood by any means, Mayo, 566 U.S. at 79, 101 USPQ2d at 1968; Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1362, 123 USPQ2d 1081, 1088 (Fed. Cir. 2017);
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ii. Using polymerase chain reaction to amplify and detect DNA, Genetic Techs. v. Merial LLC, 818 F.3d 1369, 1376, 118 USPQ2d 1541, 1546 (Fed. Cir. 2016); Ariosa Diagnostics, Inc. v. Sequenom, Inc., 788 F.3d 1371, 1377, 115 USPQ2d 1152, 1157 (Fed. Cir. 2015);
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iii. Detecting DNA or enzymes in a sample, Sequenom, 788 F.3d at 1377-78, 115 USPQ2d at 1157); Cleveland Clinic Foundation 859 F.3d at 1362, 123 USPQ2d at 1088 (Fed. Cir. 2017);
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v. Analyzing DNA to provide sequence information or detect allelic variants, Genetic Techs., 818 F.3d at 1377; 118 USPQ2d at 1546;
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Here, the claims do not contain any significant additional elements or steps beyond the observation of judicial exception(s) present when performing routine and conventional methods. Further, the active method steps are conventional and routine in the art for the reasons stated above and the claims do not amount to significantly more than the judicial exception(s). Further, just as methods comprising detecting paternal DNA sequences in particular samples by PCR was identified in Ariosa v. Sequenom as "well-known, routine, and conventional" (see first paragraph on page 13 of Ariosa Diagnostics, Inc. v. Sequenom, Inc. (Fed. Cir. 2015)) even though the prior art did not demonstrate detecting said paternal DNA sequences in said particular samples by PCR, the methods encompassed by the instant claims are well-known, routine, and conventional. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the additional elements (common methods of detecting expression and/or detecting presence or absence or mutations) are routinely performed in the art to obtain data regarding expression and characterize mutational status. In regards to “predicting", it is further noted that merely presenting results of a process otherwise unpatentable under 35 U.S.C. 101 is insufficient to establish eligibility under the statute. See FairWarning IP, LLC v. Iatric Sys., Inc., No. 2015-1985, 2016 WL 5899185, at *3 (Fed. Cir. Oct. 11, 2016) (claim unpatentable under 35 U.S.C. 101 despite recitation of the step: “providing notification if [an] event has occurred”). Moreover, “[w]hile preemption may signal patent ineligible subject matter, the absence of complete preemption does not demonstrate patent eligibility…." Ariosa Diagnostics, Inc., v. Sequenom, Inc., 788 F.3d 1371, 1379 (Fed. Cir. 2015), cert. denied, No. 15-1182, 2016 WL 1117246 (U.S. June 27, 2016). Further, “Groundbreaking, innovative, or even brilliant discovery does not by itself satisfy the § 101 inquiry.” Ass’n for Molecular Pathology v. Myriad Genetics, Inc., 133 S. Ct. 2107, 2117 (2013). The claims do not recite something “significantly more” than the judicial exception(s); rather, the claims “simply inform” the natural phenomenon to one performing routine active method steps and do not amount to significantly more than the judicial exception(s).
Conclusion
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/SEAN E AEDER/ Primary Examiner, Art Unit 1642