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
Status of Claims
Claims 1-3, 5-7, 9-11, 13-19, 22-23 and 25-26 are pending. Claims 1-2 and 5-7 are the subject of this NON-FINAL Office Action. This is the first office action on the merits.
Election/Restrictions
Applicant’s election with traverse of Group I (claims 1-2 and 5-7 ), and the species of renal/kidney cancer, detecting resistance to immune checkpoint blockade therapy and splice variants of EGFR, MCCC1 and FGD1 in the reply filed on 02/20/2026 is acknowledged. First, Applicants failed to elect the proper slice variant. The Examiner required Applicant to elect a specific variant. However, the reason Applicants could not do this for MCCC1 and FGD1 is because no such variant is disclosed (see Written Description rejection, below). For EGFR, only one is disclosed. Second, Applicants’ argument that a serious search burden does not exist is found wanting. Applicants have structured their claims to encompass any cancer, and any splice variants of the listed genes (which also encompasses both proteins and mRNA). These variables alone encompass thousands of possible combinations, each with specific splice variants for specific cancers, along with specific treatments. Applicants are simply wrong that there is not a serious search burden.
However, due to the lack of prior art for splice variants for all of EGFR, MCCC1 and FGD1 in kidney cancer, this election of species is withdrawn.
Claims 9-11, 13-19, 22-23 and 25-26 are withdrawn.
Priority
The claims receive a priority date of 11/22/2021 because this is the first priority date (PCT/US2021/060276) with ipsis litteris support for splice variants for all of the listed genes.
Claim Notes
The claims are directed to detecting any splice variant of the listed genes, either in their protein or mRNA form.
The claims are also directed to any cancer.
The following merely points out an inherent characteristic of data, but fails to recite any specific steps taken: “wherein the presence of an EGFR, FAM107B, PDZD2, COBLL1, FGD1, GAL3ST1, HPCALI, KDELC1, MCCCI, MVK, MVKbeta, PARN, PTPN14, RNASET2beta, SLC15A4, and/or SYNPO splice variant in the tissue sample indicates that the cancer is resistant to immune checkpoint blockade inhibition.” Claim 7 suffers the same defiency.
Claim Rejection - 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 1-2 and 5-7 are 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, or an abstract idea) without significantly more.
Specifically, the claims are directed to the natural phenomenon of gene splice variants. Under step 2A, prong one this is a natural phenomenon. See MPEP § 2106.04(B).
As to step 2A prong two, none of the claims recite additional elements that integrate the JE into a practical application. Specifically, claim 1 merely states that the detected splice variants “indicate” that any cancer is resistant to immune checkpoint blockade therapy. The claims fails to recite a specific treatment step, or any other step that applies this “indication.” See MPEP § 2106.04(d)(2) (“Examiners should keep in mind that in order to qualify as a “treatment” or “prophylaxis” limitation for purposes of this consideration, the claim limitation in question must affirmatively recite an action that effects a particular treatment or prophylaxis for a disease or medical condition”). At best, claim 2 states “treating with an anti-cancer therapy that is not an immune checkpoint blockade inhibitor,” however, this is so generic that it encompasses any possible therapy other than immune checkpoint blockade inhibitor based on any splice variant. See MPEP § 2106.04(d)(2) (“The treatment or prophylaxis limitation must be “particular,” i.e., specifically identified so that it does not encompass all applications of the judicial exception(s).”; “The treatment or prophylaxis limitation must have more than a nominal or insignificant relationship to the exception(s).”).
As to step 2B, no other additional elements amount to significantly more than the natural phenomenon. For example, ddPCR is so routine and conventional that it cannot add significantly more. See e.g. Coccaro et al, Digital PCR: A Reliable Tool for Analyzing and Monitoring Hematologic Malignancies, Int J Mol Sci. 2020 Apr 29;21(9):3141. doi: 10.3390/ijms21093141, pgs. 1-2 (“Since then, different systems have been invented, such as the microfluidic chamber-based BioMark Digital PCR from Fluidigm, the chip-based Quantstudio 12k/3D dPCR System from Thermo Fisher Scientific, the droplet-based QX-100/QX-200 Droplet Digital PCR (ddPCR) Systems from Bio-Rad Laboratories, the RainDrop dPCR from RainDance Technologies, the Crystal dPCR System with the Naica System from Stilla Technologies, the Clarity dPCR system from JN MedSys, and FORMULATRIX dPCR from QIAGEN. Each variation of the dPCR methodology has been demonstrated to be useful for studying cancer, yielding comparable results in regards to nucleic acid quantification, sensitivity and specificity; however, of them all, ddPCR seems to present greater diffusion as compared to the other technologies, likely because of its qualities as regards ease of use and application, and adaptability, saving time and effort. It is the digital platform most commonly used for cancer applications, and also in studies on hematologic malignancies.”).
In sum, the claims generically recite to use the natural phenomenon of gene splice variants and detect them using routine and conventional ddPCR; and at best generically treat with anything that is not an immune checkpoint blockade inhibitor. Thus, it fails to pass muster under Section 101.
Claim Rejection - 35 USC § 112- Indefiniteness
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 1-2 and 5-7 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 1 is missing a step according to the preamble, rendering the claim confusing. Specifically, the preamble states “[a] method of detecting resistance of a cancer to immune checkpoint blockade inhibition,” but fails to detect this resistance. Instead, the claim body merely states to ddPCR detect EGFR, FAM107B, PDZD2, COBLL1, FGD1, GAL3ST1, HPCALI, KDELC1, MCCCI, MVK, MVKbeta, PARN, PTPN14, RNASET2beta, SLC15A4, and/or SYNPO. No other steps are recited. Thus, it is unclear if claim 1 is missing a step.
Claim Rejection - 35 USC § 112 – Written Description
The following is a quotation 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.
Claims 1-2 and 5-7 are rejected under 35 U.S.C. 112(a) as failing to comply with the written description requirement. The claims contain subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, at the time the application was filed, had possession of the full scope of the claimed invention.
The specification does not demonstrate possession of all splice variants of every gene EGFR, FAM107B, PDZD2, COBLL1, FGD1, GAL3ST1, HPCALI, KDELC1, MCCCI, MVK, MVKbeta, PARN, PTPN14, RNASET2beta, SLC15A4, and/or SYNPO, much less associated with every cancer.
“[T]he purpose of the written description requirement is to ‘ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent specification.”’ Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353–54 (Fed. Cir. 2010) (en banc). Whether the disclosure of a patent satisfies the written description requirement is a question of fact. See id. at 1351. The test for sufficiency of the written description support is “whether the disclosure of the application relied upon reasonably conveys to those skilled in the art that the inventor had possession of the claimed subject matter as of the filing date sought.” Id. This “possession” test “requires an objective inquiry into the four corners of the specification from the perspective of a person of ordinary skill in the art.” Id. Possession shown by evidence “outside of the specification is not enough,” and “a description that merely renders the invention obvious does not satisfy the requirement.” Id. at 1352. Instead, it is the specification itself that must demonstrate possession. Id.
Where, as here, a genus is claimed using functional language to define a desired result, “the specification must demonstrate that the applicant has made a generic invention that achieves the claimed result and do so by showing that the applicant has invented species sufficient to support a claim to the functionally-defined genus.” Id. at 1349; AbbVie Deutschland GmbH v. Janssen Biotech, Inc., 759 F.3d 1285, 1299 (Fed. Cir. 2014). A “sufficient description of a genus instead requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can ‘visualize or recognize’ the members of the genus.” Ariad Pharms., 598 F.3d at 1350. Such correlations may be established “by the inventor as described in the specification,” or they may be “known in the art at the time of the filing date.” See AbbVie, 759 F.3d at 1301. And any claimed functions of the various generic terms and phrases that “merely draw[s] a fence around the outer limits of a purported genus [and] is not an adequate substitute for describing a variety of materials constituting the genus and showing that one has invented a genus and not just a species.” See Ariad, 598 F.3d at 1350.
Here, the claims encompass any and all splice variants of every listed gene, associated with any cancer; yet, at best, only one splice variant for each of EGFR, FAM107B, PDZD2, HPCAL1 and MVK is disclosed, along with a single cancer, kidney. See Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341, 1351 (Fed. Cir. 2011) (“For generic claims,” the Federal Circuit has “set forth a number of factors for evaluating the adequacy of the disclosure, including ‘the existing knowledge in the particular field, the extent and content of the prior art, the maturity of the science or technology, [and] the predictability of the aspect at issue.’”) (quoting Capon v. Eshhar, 418 F.3d 1349, 1359 (Fed. Cir. 2005)). Specifically, the specification discloses “EGFR_PR20CTF, a novel epidermal growth factor receptor aberrant splice variant that is unique to clear cell renal cell carcinoma (ccRCC) has been identified” (pg. 1, and throughout); while Tables 1 and 3-6 disclose FAM107B (10:14664173-14700032), PDZD2 (5:31995744-32000244), HPCAL1 (2:10529703-1053696) and MVK (12:110032708-110032832) in clear cell RCC. No other splice variants or their locations are provided, much less specific cancers. Each gene mRNA has multiple exons and introns, yielding innumerable possible splice variants. Moreover, the claims encompass any cancer, which is a very large number of possible cancers, each with different possible splice variant markers with different informative results. See Chen et al, Alternative splicing of EZH2 pre-mRNA by SF3B3 contributes to the tumorigenic potential of renal cancer, Clin Cancer Res. Author manuscript; available in PMC: 2018 Jul 1 (“Almost all human genes are subject to alternative splicing, a pivotal mechanism for generating protein diversity; indeed different splice isoforms from the same gene may have differing and even opposing functions. Increasing evidence suggests that tumorigenesis often involves large-scale alterations in alternative splicing. For example, SF3B1 is a crucial component of the splicing machinery, which is frequently mutated in refractory anemia with ring sideroblasts (RARS) (32), RARS associated with thrombocytosis (RARS-T), and chronic lymphocytic leukemia. Thus, the deregulation of alternative RNA splicing plays a critical role in tumor development and progression. However, the roles of spliced variants and splicing factors that control splicing dysregualtion in tumorigenesis need more investigation.”); David et al, Alternative pre-mRNA splicing regulation in cancer: pathways and programs unhinged. Genes Dev. 2010;24:2343–2364. doi: 10.1101/gad.1973010 (“Each regulatory point in the control of gene expression (which includes chromatin structure, splicing and polyadenylation of mRNA precursors, translation, and mRNA and protein stability) is subject to profound alterations during the development of most, if not all, cancers. Of all of these points in the gene expression pathway, none provides the potential for more diverse outcomes than alternative splicing (AS).”; “While the number of AS events observed to differ in cancer has grown quickly with the use of such methods, relatively few have been demonstrated to be functionally important”); Davy et al, Detecting splicing patterns in genes involved in hereditary breast and ovarian cancer, Eur J Hum Genet. 2017 Jul 26;25(10):1147–1154. doi: 10.1038/ejhg.2017.116 (“However, the complexity of splicing regulation, mentioned above, makes the interpretation of [variants of unknown significance] effects difficult.”). Combined, this yields thousands if not more possible splice variants associated with specific cancers, yielding different specific information. Given the scope of the claimed genus of splice variants and cancers, the Examiner finds that the Specification provides at most a wish or research plan, “leaving it to others to explore the unknown contours of the claimed genus.” See AbbVie Deutschland GmbH v. Janssen Biotech, Inc., 759 F.3d 1285, 1300 (Fed. Cir. 2014); see also Centocor, 636 F.3d at 1351. Thus, like in Centocor, the Specification here “at best describes a plan for making [splice variant markers for specific cancers for specific information] and then identifying those that satisfy the claim limitations,” but such a “‘mere wish or plan’ for obtaining the claimed invention is not sufficient.”
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) 1-2 and 5-7 is/are rejected under 35 U.S.C. 103 as being unpatentable over Coba et al, Abstract 2632: Increased recurrence and clinical grade in renal cell carcinomas associated with novel EGFR splice variants, Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2632, Zaman et al, Aberrant Epidermal Growth Factor Receptor RNA Splice Products Are Among the Most Frequent Somatic Alterations in Clear Cell Renal Cell Carcinoma and Are Associated with a Poor Response to Immunotherapy, Eur Urol Focus. 2019 Dec 31;7(2):373–380. doi: 10.1016/j.euf.2019.12.001, MARTIN (US20240050441), SKOG (US20190211106) and RODRIGUEZ (US20230107770), in view of Coccaro et al, Digital PCR: A Reliable Tool for Analyzing and Monitoring Hematologic Malignancies, Int J Mol Sci. 2020 Apr 29;21(9):3141. doi: 10.3390/ijms21093141.
The prior art as a whole demonstrates that it would have been obvious to a skilled artisan at the time of filing to apply familiar ddPCR detection technique to detect low-level splice variant mutations with a reasonable expectation of success.
Coba, Zaman, MARTIN, SKOG and RODRIGUEZ demonstrate that EGFR splice variants were known to be associated with renal/kidney cancer. Coba teaches
Results: We identified a EGFR gene splice variant, predominantly c.2470-188_c.2470-2, between exons 20 and 21 in RCCs subjected to the sequencing assay. Of 1075 solid tumors analyzed, the presence of the EGFR gene splice variant was observed, in any amount, within 74 of 102 RCC cases (72.5%), with the only exceptions being one multiple myeloma and sarcoma case. Using an EGFR slice variant cutoff of ≥5%, 33 of 102 (32.4%) RCC were chosen to be further investigated. Upon further analysis, 32 EGFR slice variant tumors were clear cell RCC, while 1 was papillary type II RCC. Thirty cases involving ≥5% slice variants were clinically staged revealed 6 T1, 8 T2, and 16 T3/4 cases compared to tumors with <5% of the splice variants which were staged 28 T1, 10 T2, 21 T3/4, and 8 Tx (p=.011). The RFS curve trended to worse outcomes for patients with ≥5% EGFR splice variants compared to <5% EGFR splice variants (p=.0315). All variants were identified at the RNA level without obvious corresponding DNA alterations. There was an average of 106 unique reads (average of 7.7% of all reads) for these cases supporting this variant.
Conclusion: EGFR splice variants in RCC are a relatively frequent and specific molecular alteration. This novel splice variant may prove to be significant as a druggable target or as part of a kidney cancer screening protocol.
This demonstrates a motivation to detect EGFR splice variants to determine the best therapy. Zaman teaches “Results and limitations: EGFR_pr20CTF expression was identified in 71.7% (n = 71/99) of patients with RCC in our institutional cohort and in 56.7% (n = 279/492) of patients in the TCGA cohort. EGFR_pr20CTF was found to be specific to clear cell renal cell carcinoma (ccRCC), occurring in <0.2% of non-RCC tumors (n = 2/1091). High levels of EGFR_pr20CTF correlated with lower survival at 48 mo following immunotherapy (p = 0.036). The average survival in patients with high EGFR_pr20CTF expression was <16 mo. Conclusions: The EGFR_pr20CTF RNA splice variant occurs frequently, is specific to patients with advanced ccRCC, and is associated with a poor response to immunotherapy” (Abstract). “These findings may have implications in the development of advances in screening and therapeutic exploitation strategies for this patient population. Moreover, our results warrant further investigation into whether this variant may be a biomarker for response to immunotherapy” (Conclusions). In other words, Zaman provides motivation to detect EGFR_pr20CTF RNA splice variants using PCR to determine resistance to immune checkpoint blockade therapy. Similarly, MARTIN teaches to detect EGFR splice variants (e.g., Viii, Vvi, and Vii) in renal/kidney cancer patients using e.g. PCR, and treat them with therapeutically effective amount of a compound of Formula I or its pharmaceutically acceptable salt (Claims 1 and 3, paras. 0230 and 0264). SKOG similarly teaches to detect splice variant EGFRvVI in renal/kidney cancer patients using PCR, then treat with EGFR inhibitor (Abstract, paras. 0033, 0043, 0046, 0067-68, 0076 & 0090-93). RODRIGUEZ similarly teaches “Where an EGFR splice variant isoform is not detected, the treatment methods can include or further include checkpoint inhibitors include, but are not limited to antibodies that block PD-1 (Nivolumab (BMS-936558 or MDX1106), CT-011, MK-3475), PD-L1 (MDX-1105 (BMS-936559), MPDL3280A, or MSB0010718C), PD-L2 (rHIgM12B7), CTLA-4 (Ipilimumab (MDX-010), Tremelimumab (CP-675,206)), IDO, B7-H3 (MGA271), B7-H4, TIM3, LAG-3 (BMS-986016)” (para. 0167). In other words, multiple references teach that low-level splice variants of EGFR are correlated to kidney/renal cancer treatment optimization. A skilled artisan would have been motivated to apply familiar high-sensitivity nucleic acid detection techniques to detect such low-level splice variants.
One such very familiar technique was ddPCR. This is shown by Coccaro. Coccaro teaches that “[t]he digital polymerase chain reaction (dPCR) is considered to be the third-generation polymerase chain reaction (PCR), as it yields direct, absolute and precise measures of target sequences. dPCR has proven particularly useful for the accurate detection and quantification of low-abundance nucleic acids, highlighting its advantages in cancer diagnosis and in predicting recurrence and monitoring minimal residual disease, mostly coupled with next generation sequencing” (Abstract). “Since [Vogelstein lab disclosure of dPCR], different systems have been invented, such as the microfluidic chamber-based BioMark Digital PCR from Fluidigm, the chip-based Quantstudio 12k/3D dPCR System from Thermo Fisher Scientific, the droplet-based QX-100/QX-200 Droplet Digital PCR (ddPCR) Systems from Bio-Rad Laboratories, the RainDrop dPCR from RainDance Technologies, the Crystal dPCR System with the Naica System from Stilla Technologies, the Clarity dPCR system from JN MedSys, and FORMULATRIX dPCR from QIAGEN. Each variation of the dPCR methodology has been demonstrated to be useful for studying cancer, yielding comparable results in regards to nucleic acid quantification, sensitivity and specificity; however, of them all, ddPCR seems to present greater diffusion as compared to the other technologies, likely because of its qualities as regards ease of use and application, and adaptability, saving time and effort. It is the digital platform most commonly used for cancer applications, and also in studies on hematologic malignancies” (pgs. 1-2). In fact, “Frequently, dPCR has been employed as a validation tool to corroborate data obtained with other technologies (Figure 1). In research conducted in 2019, Jespersen et al. performed ddPCR experiments to corroborate data regarding alternative splice variants of a series of candidate genes identified through exon array analysis, in order to demonstrate that specific alternatively spliced NOTCH3 isoforms display a prognostic and predictive biomarker potential in Germinal Center B-cell like (GCB) DLBCL” (pg. 10). This representative teaching demonstrates that ddPCR was routinely applied in low-abundance splice variant detection environments such as cancer splice variants. Thus, the prior art demonstrates that ddPCR to detect the EGFR splice variants of the prior art would have been the obvious application of a familiar detection system to detect familiar splice variants to achieve high sensitivity detection.
Conclusion
No claims are allowed.
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/AARON A PRIEST/Primary Examiner, Art Unit 1681
