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
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office Action has been withdrawn pursuant to 37 CFR 1.114. Applicant’s submission filed on May 14, 2026 has been entered.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Status of Claims
Claims 1-11 are currently pending. Claim 8 has been amended by Applicants’ amendment filed 04-07-2026. No claims have been added or canceled by Applicants’ amendment filed 04-07-2026.
Applicant's election without traverse of Group III, claims 8-11, directed to a method of inhibiting exosome secretion or inhibiting PD-L1 expression in cancer cells; and the election of:
Species (E): wherein the inhibiting of the endothelin receptor activity comprising treatment with one or more drugs as recited in claim 9 (claim 9), in the reply filed on August 31, 2025 was previously acknowledged.
Claims 1-7 was previously withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention, there being no allowable generic or linking claim.
Claim 10 was previously withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected species, there being no allowable generic or linking claim.
The restriction requirement was deemed proper and was made FINAL.
The claims will be examined insofar as they read on the elected species.
Therefore, claims 8, 9 and 11 are under consideration to which the following grounds of rejection are applicable.
Priority
The present application filed March 11, 2022 is a 35 U.S.C. 371 national stage filing of International Application PCT/KR2020/012189, filed on September 9, 2020, which claims the benefit of
Republic of Korea of Patent Application No. 10-2019-0112696, filed September 11, 2019.
Acknowledgment is made of Applicant's claim for foreign priority based on an application filed in the Republic of Korea on September 11, 2019.
Acknowledgment is made of Applicant’s filing of a certified English Translation of KR-2019-0112696 on December 3, 2025.
Declaration
The Examiner acknowledges receiving a Declaration under 37 CFR § 1.130(a), executed by Moon-Chang Baek, Eun-Ju Im, and Chan-Hyeong Lee on December 2, 2025, and filed December 3, 2025 (hereinafter the “Baek decl.”). The Baek decl. has been considered.
Withdrawn Objections/Rejections
Applicants’ amendment and arguments filed April 7, 2026 are acknowledged and have been fully considered. The Examiner has re-weighed all the evidence of record. Any rejection and/or objection not specifically addressed below are herein withdrawn.
Claim Rejections - 35 USC § 112(d)
The rejection of claim 9 is withdrawn under 35 U.S.C. 112(d) as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends due to Applicant’s amendment of claim 8, in the reply filed 04-07-2026.
In view of the withdrawn rejection, Applicant’s arguments are rendered moot.
Claim Rejections - 35 USC § 102
The rejection of claims 8, 9 and 11 is withdrawn under 35 U.S.C. 102(a)(1)/102(a)(2) as being anticipated by Im et al. (hereinafter “Im”) (Nature Communications, 2019, 10(1387), 1-17).
Im does not specifically exemplify PD-L1.
In view of the withdrawn rejection, Applicant’s arguments are rendered moot.
Maintained Objections/Rejections
Claim Rejections - 35 USC § 112(b)
The rejection of claims 8, 9 and 11 is maintained under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which applicant regards as the invention.
Claims 8 and 11 are indefinite for the recitation of the terms “the cultured cancer cells” and “the cancer cells” such as recited in claim 8, lines 6-9. There is insufficient antecedent basis for the terms “the cultured cancer cells” and “the cancer cells” because claim 8, lines 2 and 4 recite the terms “cancer cells” and “culturing cancer cells.” Moreover, it is unclear which cells are used in the steps of the method, for example, it is unclear whether the step of “measuring expression in the cancer cells” is carried out with primary cancer cells, with in vitro cultured cancer cells, and/or with cultured cancer cells and, thus, the metes and bounds of the claim cannot be determined.
Claim 8 is indefinite for the recitation of the term “measuring PD-L1 expression in the cancer cells or on surfaces of exosomes secreted by the cancer cells by immunoblot analysis or quantitative polymerase chain reaction” such as recited in claim 8, lines 7-8 because measuring PD-L1 expression via PCR requires measuring mRNA, wherein PD-L1 mRNA is present within an exosome, but PD-L1 mRNA is not present on surface of exosomes secreted cancer cells as evidenced by Ayala-Mar (pg. 1, col 2, last partial paragraph; and pg. 7, col 1, second full paragraph). Additionally, it is unclear how PCR is used to quantify and/or analyze PD-L1 expression as recited in claim 8 because immunoblot analysis measures proteins and not mRNA. Moreover, it is known that most immune checkpoint inhibitors targeting PD-L1 have no effect on prostate cancer patients as evidenced by Liu (pg. 6, col 2, last partial paragraph); and a tumor can be PD-L1 positive or negative for surface PD-L1 expression as evidenced by Ribas (Abstract; and pg. 2836, col 1, first full paragraph). It appears as though not all cancer cells as encompassed by instant claim 8 will demonstrate reduced PD-L1 expression as compared to vehicle-treated control and, thus, the metes and bounds of the claim cannot be determined.
Claim 8 is indefinite for the recitation of the term “vehicle-treated control” such as recited in claim 8, line 11 because claim 8 does not recite the presence of a “vehicle” in the steps of the method. Moreover, the claim does not recite whether the control comprises cells, cancer cells, cultured cancer cells, etc., such that the identity and/or conditions regarding the “vehicle-treated control” are completely unclear.
Claim 9 is indefinite insofar as it ultimately depends from instant claim 8.
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.
Please Note: the references have been modified slightly in view of Applicant’s amendments and arguments in the reply filed 04-07-2026.
The rejection of claims 8, 9 and 11 is maintained 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. An analysis with respect to the claims as a whole reveals that they do not include additional elements that are sufficient to amount to significantly more than the judicial exception. See; Alice Corp. Pty. Ltd. v. CLS Bank Int’l, 134 S. Ct. 2347, 110 U.S.P.Q.2d 1976 (2014); Ass’n for Molecular Pathology v. Myriad Genetics, Inc., 133 S. Ct. 2107, 2116, 106 U.S.P.Q.2d 1972 (2013); Mayo Collaborative Svcs. v. Prometheus Laboratories, Inc., 132 S. Ct. 1289, 101 U.S.P.Q.2d 1961 (2012). See also 2014 Interim Guidance on Patent Subject Matter Eligibility, available at http://www.gpo.gov/fdsys/ pkg/FR-2014-12-16/pdf/2014-29414.pdf (“2014 Interim Guidance”), and the Office’s examples to be considered in conjunction with the 2014 Interim Guidance in examination of nature-based products, available online at: http://www.uspto.gov/patents/law/exam/mdc_examples_ nature-based_products.pdf (“Nature-Based Products Examples”). This rejection is proper.
Analysis of subject-matter eligibility under 35 U.S.C. § 101 requires consideration of three issues: (1) whether the claim is directed to one of the four categories recited in §101; (2) whether the claim recites or involves a judicial exception (i.e., a law of nature, natural phenomenon, or natural product); and (3) whether the claim as a whole recites something that amounts to significantly more than the judicial exception. In the instant case, the claims are directed to a natural phenomenon and an abstract idea, including determining a natural change in PD-L1 expression occurs in cultured cancer cells and/or on the surface of exosomes secreted by cultured cancer cells upon contact with an endothelin receptor inhibitor, and analysis by immunoblot and/or qPCR. Therefore, they must each be considered to determine whether, given their broadest reasonable interpretation, they amount to significantly more than the judicial exception.
The claimed invention is not directed to patent eligible subject matter. Based upon an analysis with respect to the claims as a whole, claims 8, 9 and 11 do not recite something significantly different than a judicial exception. The rationale for this determination is explained below:
In the instant case, claim 8 is broadly directed to a method for inhibiting exosome secretion or inhibiting PD-L1 expression in cancer cells in vitro, the method comprising: contacting the cancer cells in vitro with an endothelin receptor inhibitor that inhibits endothelin receptor activity in the cancer cells; and determining that the contacting reduces a number concentration of exosomes secreted by the cancer cells as measured by nanoparticle tracking analysis, or reduces the PD-L1 expression in the cancer cells or on surfaces of the exosomes secreted by the cancer cells as measured by immunoblot analysis or qPCR, relative to an untreated control.
Beginning with Step I of the analysis, which asks whether the claimed invention falls within a statutory category, such that the instant claims are directed to a process, thus, the instant claims are directed to a statutory category. Step I [YES].
Proceeding to Step IIA – Prong One of the analysis, which asks if the claimed invention is directed to a judicial exception, such that claims 8, 9 and 11 are drawn to a natural phenomenon in the form of a natural correlation between contacting cancer cells with an endothelin receptor inhibitor, and a reduction in: (i) endothelin receptor activity in the cancer cells, and (ii) PD-L1 expression in the cancer cells, and to an abstract idea in the form of mathematical concepts, such as mathematical relationships, formulas or equations, and/or calculations (e.g., measuring a reduction in endothelin receptor activity; immunoblot analysis; PCR analysis; determining that PD-L1 expression is reduced relative to a vehicle-treated control, etc.); as well as, mental process including observation, judgement and opinion (e.g., determining that PD-L1 expression is reduced, etc.).
Thus, the claims recite a natural phenomenon, and an abstract idea, which falls within the groupings of abstract ideas enumerated in the 2019 PEG including encompassing mathematical concepts, equations, and calculations that can be carried out in the human mind, and/or by using a general computer that performs routine and conventional functions, as well as, mental process performed in the human mind including concepts such as observation, evaluation, judgement, and/or opinion. Thus, under the revised Step IIA analysis, the claims are directed to a natural phenomenon, and to an abstract idea. Step IIA – Prong One [YES].
Step IIA - Prong Two asks whether the claim recites additional elements that integrate the exception into a practical application of the exception. In the instant case, the claims are directed to a judicial exception in the form of a natural phenomenon and an abstract idea. Claim 8 recites: “a method for inhibiting programmed cell death-ligand I (PD-L1) expression in cancer cells in vitro, the method comprising: culturing cancer cells in vitro; contacting the cultured cancer cells in vitro with an endothelin receptor inhibitor that inhibits endothelin receptor activity in the cancer cells” in lines 1-6; “measuring PD-L1 expression in the cancer cells or on surfaces of exosomes secreted by the cancer cells by immunoblot analysis or quantitative polymerase chain reaction” in lines 7-8; and “determining that the PD-L1 expression in the cancer cells is reduced relative to a vehicle-treated control” in lines 9-11. These limitations simply describe a process of collecting and analyzing information, which is analogous to “obtaining and comparing intangible data” (i.e. CyberSource Corp. v. Retail Decisions, Inc., 654 F.3d 1366, 99 U.S.P.Q.2d 1690 (Fed. Cir. 2011)); as well as, “collecting information, analyzing it, and displaying certain results of the collection analysis” (i.e. Electric Power Group, LLC, v. Alstom, 830 F.3d 1350, 119 U.S.P.Q.2d 1739 (Fed. Cir. 2016)). Moreover, many of Applicant’s process steps can be practiced as a mental process performed in the human mind, by pen and paper, or through the use of a generic computer, for example, “comparing information regarding a sample or test subject to a control or target data” (i.e. Univ. of Utah Research Found. v. Ambry Genetics Corp. (Also known as In re BRCA1– and BRCA2–Based Hereditary Cancer Test Patent Litigation), 774 F.3d 755, 113 U.S.P.Q.2d 1241 (Fed. Cir. 2014) or Association for Molecular Pathology v. USPTO (Also known as Myriad CAFC), 689 F.3d 1303, 103 U.S.P.Q.2d 1681 (Fed. Cir. 2012)). Hence, these limitations are akin to an “abstract idea itself” which was at issue in Alice Corp. and has been identified among non-limiting examples to be an abstract idea. Additionally, the dependent limitations of claims 9 and 11 also suffer from the same issue. In other words, the dependent limitations do not rectify the rejection of the independent claim. By way of example, the limitations of claim 9 recites, “wherein the endothelin receptor inhibitor is selected from the group consisting of…sulfisoxazole…ambrisentan…and bosentan” which clearly resembles “comparing information regarding a sample or test subject to a control or target data” (i.e. Univ. of Utah Research Found. v. Ambry Genetics Corp. (Also known as In re BRCA1– and BRCA2–Based Hereditary Cancer Test Patent Litigation), 774 F.3d 755, 113 U.S.P.Q.2d 1241 (Fed. Cir. 2014) or Association for Molecular Pathology v. USPTO (Also known as Myriad CAFC), 689 F.3d 1303, 103 U.S.P.Q.2d 1681 (Fed. Cir. 2012)). Thus, the claims do not integrate the judicial exceptions into a practical application of the exceptions. Step IIA – Prong Two [NO].
Proceeding to Step IIB of the analysis: the question then becomes what element or what combination of elements is sufficient to amount to significantly more than the abstract idea?
The instant independent claim is recited at a high level of generality, such that substantially all practical applications of the judicial exception are covered. For instance, claim 8 is recited without any specificity as to the method of culturing the cancer cells including the culture conditions; the identity and number of cancer cells; the method of contacting; the endothelin receptor inhibitor (e.g., ambrisentan, bosentan, macitentan, sulfisoxazole, etc.); whether all of the cancer cells are in vitro cancer cells; whether the cells can be in vivo cancer cells; the endothelin receptor inhibited (e.g., ETA, ETB, dual inhibitor, etc.); what is measured for PD-L1 expression (e.g., protein, peptides, mRNA, DNA, RNA, cDNA, etc.); the length of time and conditions under which the cells are maintained in contact with the inhibitor; the method of preparing and/or purifying the cells prior to analysis; the particular immunoblot analysis (e.g., Western blot, Northern blot, Dot & Slot blot, etc.); the conditions for immunoblot analysis; the conditions for the qPCR; the identity of the vehicle-treated control; the specific vehicle; etc. The claims amount to nothing more than contacting cancer cells with a drug and/or environmental changes, determining a change in the expression of PD-L1 in the cancer cells, or changes in the concentration of exosomes secreted by the cancer cells as compared to untreated normal cells or untreated cancer cells, wherein the steps of the method are well-known in the art.
For example, it was known that PD-L1 on the surface of tumor cells binds its receptor PD-1 on effector T cells, thereby suppressing their activity, wherein antibody blockade of PD-L1 can activate an anti-tumor immune response leading to durable remissions in a subset of cancer patients, such that alternative mechanism of PD-L1 activity involving its secretion in tumor-derived exosomes is described, wherein removal of exosomal PD-L1 inhibits tumor growth, even in models resistant to anti-PD-L1 antibodies; and it is known that exosomal PD-L1 from the tumor suppresses T cell activation as evidenced by Poggio (Cell, 2019,177, 414-427; Abstract); and that ALIX depletion results in prolonged and enhanced stimulation induced EGFR activity as well as defective PD-L1 trafficking through the MVB, reduced exosomal secretion, and its redistribution to the cell surface; and that increased surface PD-L1 expression confers an EGFR-dependent immunosuppressive phenotype on ALIX-depleted cells, such that there is an inverse association between ALIX and PD-L1 expression was observed in human breast cancer tissues, while an immuno-competent mouse model of breast cancer revealed that ALIX-deficient tumors are larger and show an increased immunosuppressive environment, wherein the data suggest that ALIX modulates immunosuppression through regulation of PD-L1 and EGFR may present a diagnostic and therapeutic target for BLBC was known in the art as evidenced by Moneypenny (Cell Reports, 2018, 24, 630-641; Abstract). Moreover, methods for identifying sulfisoxazole (SFX) as an inhibitor of small extracellular vesicles (sEV) secretion from breast cancer cells through interference with endothelin receptor A (ETA), wherein SFX is an FDA-approved oral antibiotic, showed significant antitumor and anti-metastatic effects in mouse models of breast cancer xenografts, the reduced expression of proteins involved in biogenesis and secretion of sEV, and triggered co localization of multivesicular endosomes with lysosomes for degradation; as well as, screening the library of FDA-approved drugs, we identified sulfisoxazole (SFX), an oral antibacterial drug, as a specific inhibitor of the biogenesis and secretion of sEV from breast cancer cells, resulting in the effective suppression of breast cancer growth and metastasis without significant toxicity; and that endothelin receptor A (ETA), which was found to be critically associated with sEV biogenesis and secretion in breast cancer cells was known in the art as evidenced by Im (Nature Communications, 2019, 10(1387), 1-17; of record; abstract; and pg. 2, col 1, third full paragraph); and it was known that tumor-derived exosomes (TDEs) are key players involved in tumor growth, tumorigenesis, angiogenesis, dysregulation of immune cells and immune escape, metastasis, and resistance to therapies, as well as in promoting anti-tumor response as evidenced by Bae (Genes & Cancer, 2018, 9(3-4), 87-100; Abstract). Furthermore, it was known that exosomes containing PD-L1 could predict immunotherapy responses, wherein immune-evasion mechanism may help explain the differences in responses to immunotherapy. Additionally, PD-1, found on the surface of T cells, regulates the immune system’s response to cells of the human body acting to inhibit T cells from attacking other cells in the body. However, when PD-1 is bound to PD-L1, the T–cell killing is inhibited. Tumor cells evade immune surveillance by upregulating the surface expression of PD-L1 - which, when bound to PD-1 on T cells, initiates the anticancer response (or immune checkpoint response). Human PD-L1 was identified on the circulating exosomes from mice bearing human melanoma xenografts, but not the control mice. Not only did the level of circulating PD-L1+ exosomes correlate with tumor size, but adding PD-L1+ exosomes accelerated the progression of melanoma tumors. In addition, the researchers found that the PD-L1+ exosomes inhibit the T cells as evidenced by LeMieux (Clinical OMICs, 2018, 5(5), 1-4; pg. 2, fifth and sixth full paragraphs). Additionally, it was known that blocking ET receptors by macitentan hampers CLL cells migration, facilitates CLL cell death and overcomes survival advantage mediated by micro-environmental elements, wherein macitentan interferes with B-cell receptor (BCR) activation and improves ABT-199 effects on CLL cells in contact with stromal supporting cells; and that macitentan impairs CLL cells proliferation, interferes with β-catenin signaling and reduces VEGF expression in CLL cells by decreasing hypoxia-inducible factor-1 (HIF-1α) accumulation, suggesting the possibility to interfere with ET receptors activity using macitentan as a possible novel therapeutic strategy for CLL patients. Moreover, levels of ET-1 were measured by quantitative reverse-transcription PCR and ET-1 protein levels quantified by flow cytometry (MFIR); and that ET-1 mRNA and protein expression in CLL cells was reduced by in vitro treatment with ibrutinib (Figures 1E and 1F), which strongly suggest a correlation between ET-1 expression and CLL progression in vivo as evidenced by Maffei (Oncotarget, 2017, 8(52), 90013-90027; pg. 90014, col 2, second full paragraph; and pg. 90015, col 2, first full paragraph; and Figure 1); and it was known that nanoparticle tracking analysis permits the determination of both the size distribution and relative concentration of microvesicles, including exosomes, in the supernatants of cultured cells and biological fluids as evidenced by Soo (Abstract). Moreover, in vitro and in vivo cancer cells to photodynamic therapy was a massive production and emission of extracellular vesicles (EVs) only 1 hour after the photo-activation, thousands of vesicles per cell were emitted in the extracellular medium. A similar effect has been found after treatment with Doxorubicin (chemotherapy) after the treatment; and the released EVs could transfer extracellular membrane components, drugs and even large intracellular objects to naïve target cells, such that in vivo, photodynamic treatment and chemotherapy increased the levels of circulating EVs several fold, confirming the vast induction of cancer cell vesiculation triggered by anti-cancer therapies as evidenced by Aubertin (Scientific Reports, 2016, 6(35376), 1-11; Abstract); and it was known that epithelial ovarian cancer (EOC), activation of endothelin-1 (ET-1)/endothelin A receptor (ETAR) and ET-1/ETBR signaling is linked to many tumor promoting effects, such as proliferation, angiogenesis, invasion, metastasis and chemoresistance as evidenced by Soo (Immunology, 2012, 136, 192-197; Abstract). Thus, the claims as a whole simply append well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality to the judicial exception, wherein the steps are well-understood, routine and conventional activities previously known to the industry, as discussed in Alice Corp., 134 S. Ct. at 2359-60, 110 USPQ2d at 1984 (see MPEP § 2106.05(d)). Step IIA [YES].
In sum, when the relevant factors are analyzed, the claims as a whole do NOT recite additional elements that amount to significantly more than the judicial exception itself. Accordingly, claim 8 DOES NOT qualify as eligible subject matter.
Dependent claims 9 and 11 when analyzed as a whole are held to be patent ineligible under 35 U.S.C. 101 because they do not add anything that makes the natural phenomenon in claim 11, significantly different. For example, claim 11 encompasses the method of claim 8, “wherein the cancer cells are breast cancer cells”, but it does not add anything that makes the natural phenomenon and abstract idea in claim 8 significantly different.
In light of the above consideration and the new guidance, claims 8, 9 and 11 are non-statutory. This rejection is newly recited as necessitated by the new Guidance set forth in the Memorandum of July 30, 2015 updating the June 25, 2014 guidance (see June 25, 2014 memorandum from Deputy Commissioner for Patent Examination Policy Andrew Hirshfeld titled Preliminary Examination Instructions in view of the Supreme Court Decision in Alice Corporation Pty. Ltd. v. CLS Bank International, et al. (Alice Corp. Preliminary Examination Instructions) and the Revised Patent Subject Matter Eligibility Guidance (See, Federal Register, vol. 84, No. 4, January 7, 2019).
Response to Arguments
Applicant’s arguments filed April 7, 2026 have been fully considered but they are not persuasive. Applicants essentially assert that: (a) none of the steps of culturing, contacting and measuring is a mental process, such that none of the activities of claim 1 can be performed “in the human mind” or “by pen and paper” (Applicant Remarks, pg. 11, fifth through seventh full paragraphs; and pg. 12, first full paragraph); (b) the claimed method involves a physical transformation of matter, where cancer cells are physically altered by contact with an endothelin receptor inhibitor, resulting in changes in PD-L1 expression (Applicant Remarks, pg. 12, first full paragraph); (c) the claims integrate any alleged exception into a practical application (e.g., the identification of endothelin receptor inhibitors that reduce PD-L1 expression in cancer cells), wherein the Specification illustrates this (pg. 3, lines 5-13) (Applicant Remarks, pg. 12, Step 2A); and (d) the claims recite an inventive concept, the discovery that endothelin receptor inhibitors reduce PD-L1 expression in cancer cells is a novel finding not previously disclosed in the art (Applicant Remarks, pg. 13, first full paragraph).
Regarding (a), Applicant’s assertion that none of the steps of culturing, contacting and measuring is a mental process, such that none of the activities of claim 1 can be performed “in the human mind” or “by pen and paper”, is not found persuasive. Contrary to Applicant’s assertion, the Examiner suggests that instant claim 1 actually recites four (4) steps (e.g., culturing, contacting, measuring, and determining). It is noted that Applicant has not provided any arguments with respect to the rejection of claims 8, 9 and 11 as being directed to a natural phenomenon and an abstract idea (including mathematical concepts). Applicant has merely argued that claim 8 does not recite a mental process. Regarding this assertion (including a mental process carried out in the human mind or by use of a pen and paper), the Examiner contends that step of “determining that PD-L1 expression in the cancer cells is reduced relative to a vehicle control” is a mental process. Thus, the claims are directed to a natural phenomenon and an abstract idea including mathematical concepts and mental processes. The rejection is maintained.
Regarding (b), Applicant’s assertion that the claimed method involves a physical transformation of matter, where cancer cells are physically altered by contact with an endothelin receptor inhibitor, resulting in changes in PD-L1 expression, is not found persuasive. As provided in MPEP § 2106.05(c), the physical object or substance must be specifically identified; and the “transformation" of an article means that the "article" has changed to a different state or thing. As an example, the MPEP cites Tilghman v. Proctor, wherein fat and water are transformed into fat acids and glycerin. To that point, instant claims does not recite any specific physical changes; and/or provide a specific amount of reduction in PD-L1 expression, such that the nature of the transformation does not integrate the article into a practical application of the judicial exception; and it does not pose meaningful limits on the execution of the claimed method steps. The instant claims refer to transformations that do not distinguishes them from well understood, routine, and conventional data gathering activity engaged in by scientists prior to Applicant’s invention, and at the time the application was filed (e.g., determining whether the expression of a protein or nucleic acid has changed). The Examiner contends that the cultured cells have not been physically transformed within the meaning of MPEP § 2106.05(c). Thus, the rejection is maintained.
Regarding (c), Applicant’s assertion that the claims integrate any alleged exception into a practical application (e.g., the identification of endothelin receptor inhibitors that reduce PD-L1 expression in cancer cells), wherein the Specification illustrates this, is not found persuasive. Please note that, although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26USPQ2d 1057 (Fed. Cir. 1993). As an initial matter, the instant claims do not recite “identifying endothelin receptor inhibitors that reduce PD-L1 expression in cancer cells”. Quite the contrary. Instant claim 8 recites that all endothelin inhibitors will reduce PD-L1 expression in any cancer cell and/or on the surface of any exosome secreted by the cancer cells. Moreover, one of ordinary skill in the art could not make and use the invention based on the instant claims. Instant claim 8 does not recite any specific type of cancer cell (e.g., breast cancer cells, PD-L1 negative tumors, colorectal cancer cells, skin cancer cells, optic glioma cells, etc.); any specific method of culturing; method of contacting; PD-L1 measured (e.g., RNA, DNA, proteins, peptides, etc.); no specific endothelin receptor inhibitor (ETA-specific. ETB-specific, dual ETA/B, ET3, etc.) including an inhibitor having a particular level of activity (e.g., 1M, 1uM, 1nM, etc.); vehicle-treated control, etc. Based on the broadness of the claims, one of ordinary skill in the art could not use the invention as recited for any practical application. The claims do not integrate the judicial exception into a practical application of the exception. Thus, the rejection is maintained.
Regarding (d), please see the discussion supra regarding the Examiner’s response to Applicant’s arguments. Additionally,
MPEP § 2112(I) states:
"[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer." Atlas Powder Co. v. IRECO Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977). In In re Crish, 393 F.3d 1253, 1258, 73 USPQ2d 1364, 1368 (Fed. Cir. 2004), the court held that the claimed promoter sequence obtained by sequencing a prior art plasmid that was not previously sequenced was anticipated by the prior art plasmid which necessarily possessed the same DNA sequence as the claimed oligonucleotides. The court stated that, "just as the discovery of properties of a known material does not make it novel, the identification and characterization of a prior art material also does not make it novel." Id. See also MPEP § 2112.01 with regard to inherency and product-by-process claims and MPEP § 2141.02 with regard to inherency and rejections under 35 U.S.C. 103.
MPEP § 2112(II) indicates:
there is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the time of invention, but only that the subject matter is in fact inherent in the prior art reference. Schering Corp. v. Geneva Pharm. Inc., 339 F.3d 1373, 1377, 67 USPQ2d 1664, 1668 (Fed. Cir. 2003) (rejecting the contention that inherent anticipation requires recognition by a person of ordinary skill in the art before the critical date and allowing expert testimony with respect to post-critical date clinical trials to show inherency); see also Toro Co. v. Deere & Co., 355 F.3d 1313, 1320, 69 USPQ2d 1584, 1590 (Fed. Cir. 2004) ("[T]he fact that a characteristic is a necessary feature or result of a prior-art embodiment (that is itself sufficiently described and enabled) is enough for inherent anticipation, even if that fact was unknown at the time of the prior invention."); Abbott Labs v. Geneva Pharms., Inc., 182 F.3d 1315, 1319, 51 USPQ2d 1307, 1310 (Fed.Cir.1999) ("If a product that is offered for sale inherently possesses each of the limitations of the claims, then the invention is on sale, whether or not the parties to the transaction recognize that the product possesses the claimed characteristics."); Atlas Powder Co. v. IRECO, Inc., 190 F.3d 1342, 1348-49, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999) ("Because ‘sufficient aeration’ was inherent in the prior art, it is irrelevant that the prior art did not recognize the key aspect of [the] invention.... An inherent structure, composition, or function is not necessarily known."); SmithKline Beecham Corp. v. Apotex Corp., 403 F.3d 1331, 1343-44, 74 USPQ2d 1398, 1406-07 (Fed. Cir. 2005).
Applicant’s assertion that the claims recite an inventive concept, the discovery that endothelin receptor inhibitors reduce PD-L1 expression in cancer cells is a novel finding not previously disclosed in the art, is not found persuasive. As an initial matter, the claims recite an inherent characteristic of cancer cells, such that they recite a natural phenomenon. Moreover, as discussed in the Office Action mailed February 24, 2026, recent research suggests that sulfisoxazole may not reduce the amount of EVs in cancer cells as reported by Im et al. as evidenced by Fonseka (pg. 1, col 1, first full paragraph; and pg. 4, col 1, Isolation of EVs). Furthermore, in addition to being an inherent characteristic, it is known in the art that a tumor can be PD-L1 positive or negative for surface PD-L1 expression as evidenced by Ribas (Abstract; and pg. 2836, col 1, first full paragraph); and it has been demonstrated by multiplex immunofluorescence assays that melanoma cells in some patients can be negative for PD-L1 as evidenced by Zaretsky (pg. 822, first partial paragraph). Additionally, it is known that a mechanism has been identified by which absent or low levels of tumor cell PD-L1 commonly found in solid tumors, can confer resistance to chemotherapy as evidenced by Bangor (pg. 2, first full paragraph). Once again, the claims are directed to a natural phenomenon and an abstract idea. Thus, Applicant’s asserted ‘discovery’ that “endothelin receptor inhibitors reduce PD-L1 expression in cancer cells” appears to represent a recognition of an inherent characteristic that may, or may not, occur in all cancer cells in response to contact with any endothelin inhibitor having any specificity and/or level of receptor activity. The claim remains rejected.
New Objections/Rejections
Claim Rejections - 35 USC § 103
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 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 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
Claims 8, 9 and 11 are rejected under 35 U.S.C. 103 as being unpatentable over DeFougerolles et al. (hereinafter “DeFougerolles”) (US Patent No. 10745704, issued August 18, 2020; also US20190048352, published February 14, 2019) in view of Aubert et al. (hereinafter “Aubert”) (Journal of Medicinal Chemistry, 2016, 59, 8168-8188).
Regarding claims 8, 9 and 11, DeFougerolles teaches that the invention relates to double-stranded ribonucleic acid (dsRNA) compositions targeting the CD274/PD-L1 gene, and methods of using such dsRNA compositions to inhibit expression of CD274/PD-L1 (interpreted as reducing PD-L1 expression, claim 8) (Abstract). DeFougerolles teaches that the invention provides methods for treating, preventing, reversing, or managing pathological processes mediated by CD274/PD-L1 expression, such as a tumor or other malignancy, wherein the method includes administering to a patient in need of such treatment, prevention, reversal, or management a therapeutically or prophylactically effective amount of one or more of the iRNAs featured in the invention; wherein the patient has a tumor or a hematological malignancy; and wherein administering the iRNA targeting CD274/PD-L1 alleviates or relieves the severity of at least one symptom of a CD274/PD-L1-mediated disorder in the patient, such as high tumor burden, development of metastasis, or tumor or lymphoma cell proliferation (col 5, lines 45-58). DeFougerolles teaches pharmaceutical compositions featured in the invention include (a) one or more iRNA compounds and (b) one or more biologic agents which function by a non-RNAi mechanism (col 79, lines 63-67). DeFougerolles teaches that toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals (interpreted as cell culture, claim 8) (col 80, lines 4-6). DeFougerolles teaches that the iRNAs described herein can be administered in combination with other known agents effective in treatment of pathological processes mediated by CD274/PD-L1 expression (interpreted as administering a combination of PD-L1 agents, claim 8) (col 80, lines 33-36). DeFougerolles teaches that the invention relates in particular to the use of an iRNA targeting CD274/PD-L1 and compositions containing at least one such iRNA for the treatment of a CD274/PD-L1-mediated disorder or disease including a composition containing an iRNA targeting a CD274/PD-L1 gene is used for treatment of a cancer, which refers to any of various malignant neoplasms characterized by the proliferation of anaplastic cells that tend to invade surrounding tissue and metastasize to new body sites and also refers to the pathological condition characterized by such malignant neoplastic growth such as a tumor or hematological malignancy, and includes but is not limited to, all types of lymphomas/leukemias, carcinomas and sarcomas, such as those cancers or tumors found in the anus, bladder, bile duct, bone, brain, breast, cervix, colon/rectum, endometrium, esophagus, eye, gallbladder, head and neck, liver, kidney, larynx, lung, mediastinum (chest), mouth, ovaries, pancreas, penis, prostate, skin, small intestine, stomach, spinal marrow, tailbone, testicles, thyroid and uterus; as well as, leukemias or cancers of the blood (interpreted as combining iRNA and an additional PD-L1 agent for the treatment of cancer; and breast cancer cells, claims 8 and 11) (col 80, lines 43-67). DeFougerolles teaches the use of an iRNA targeting CD274/PD-L1 and compositions containing at least one such iRNA for the treatment of an infectious disease, such as hepatitis B or a chronic bacterial infection, such that the method includes administration of a dsRNA targeting CD274/PD-L1 is administered in combination with an antibacterial agent including sulfisoxazole; sulfisoxazole acetyl; and sulfisoxazole diolamine (interpreted as an contacting cancer cells with an endothelin receptor antagonist; and sulfisoxazoles, claims 8 and 9) (col 87, lines 7-9 and 15-17; and col 89, lines 12-13). DeFougerolles teaches that the iRNA agent includes double-stranded ribonucleic acid (dsRNA) molecules for inhibiting the expression of a CD274/PD-L1 gene in a cell or mammal, e.g., in a human having a cancer or infectious disease and where the dsRNA, upon contact with a cell expressing the CD274/PD-L1 gene, inhibits the expression of the CD274/PD-L1 gene by at least 10% as assayed by, for example, a PCR or branched DNA (bDNA)-based method, or by a protein-based method, such as by Western blot; and that expression of a CD274/PD-L1 gene in cell culture, such as in COS cells, HeLa cells, primary hepatocytes, HepG2 cells, primary cultured cells or in a biological sample from a subject can be assayed by measuring CD27 4/PD-L1 mRNA levels, such as by bDNA or TaqMan assay, or by measuring protein levels, such as by immunofluorescence analysis, using, for example, Western blotting or flow cytometric techniques (interpreted as cultured cancer cells; measuring PD-L1 expression; PCR or Western blot analysis; and reduced expression of PD-L1, claim 8) (col 18, lines 1-4 and 9-23). DeFougerolles teaches angiogenesis inhibitors for use in the method including Bevacizumab (Avastin), sunitinib (Sutent), and sorafenib (Nexavar), CP-54 7,632 (3-(4-Bromo-2,6-difluoro-benzyloxy )-5-[3-( 4-pyrrolidin 1-yl-butyl)-ureido]-isothiazole-4-carboxylic acid amide hydrochloride, AG13736, AG28262, SU5416, SU11248, SU6668, ZD-6474, ZD4190, CEP-7055, PKC 412, AEE788 AZD-2171), NEXAVAR, (BAY 43-9006, sorafenib, vatalanib (also known as PTK-787, ZK-222584), MACUGEN (pegaptanib octasodium, NX-1838, EYE-001, IM862, etc. (interpreted as angiogenesis inhibitors mediated by ET1) (col 83, lines 47-61).
DeFougerolles does not specifically exemplify additional endothelin receptor inhibitors and/or cancer treatment combinations (claim 9, in part).
Regarding claim 9 (in part), Aubert teaches that the endothelin axis and in particular the two endothelin receptors, ETA and ETB, are targets for therapeutic intervention in human diseases, wherein endothelin-receptor antagonists are in clinical use to treat pulmonary arterial hypertension and have been under clinical investigation for the treatment of several other diseases, such as systemic hypertension, cancer, vasospasm, and fibrogenic diseases (Abstract). Aubert teaches that endothelin antagonists include sitaxsentan, avosentan, ambrisentan, darusentan, edonentan, atrasentan, claszosentan, nebentan, RO-462005, clazosentan, zibotentan, BQ-123, bosentan, macitentan, darusentan, TaK-044, tezosentan, T-0201, SB209670, and enrasentan (pg. 8171, Table 1; and pg. 8172, Table 2).
“It is prima facie obvious to combine prior art elements according to known methods to yield predictable results; the court held that, "…a conclusion that a claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination would have yielded nothing more than predictable results to one of ordinary skill in the art. KSR International Co. v. Teleflex Inc., 550 U.S. ___, ___, 82 USPQ2d 1385, 1395 (2007); Sakraida v. AG Pro, Inc., 425 U.S. 273, 282, 189 USPQ 449, 453 (1976); Anderson’s-Black Rock, Inc. v. Pavement Salvage Co., 396 U.S. 57, 62-63, 163 USPQ 673, 675 (1969); Great Atlantic & P. Tea Co. v. Supermarket Equipment Corp., 340 U.S. 147, 152, 87 USPQ 303, 306 (1950)”. Therefore, in view of the benefits of treating pathological diseases including cancer, systemic hypertension, vasospasm, and fibrogenic disease as exemplified by Aubert, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to modify the method of treating patients and/or cells including cancer cells with a combination of one or more iRNAs mediated by CD274/PD-L1 and an antibacterial agent such as sulfisoxazole, acetyl sulfisoxazole, and sulfisoxazole diolamine as disclosed by DeFougerolles to include other endothelin receptor inhibitors having different receptor selectivities such as being ETA-selective, ETB selective, or dual ETA/ETB antagonists including bosentan, ambrisentan and/or macitentan as taught by Aubert with a reasonable expectation of success in using the known agents taught by Aubert in the combination therapies of disclosed by DeFougerolles to treat, prevent, reverse, and/or manage a cancer including a tumor, a malignancy, and/or cancer cell metastasis; and/or in using cultured cells including cancer cells to target CD274/PD-L1 to identify combination therapies that will alleviate or relieve the severity of at least one symptom of a CD274/PD-L1-mediated disorder.
Thus, in view of the foregoing, the claimed invention, as a whole, would have been obvious to one of ordinary skill in the art at the time the invention was made. Therefore, the claims are properly rejected under 35 USC §103 as obvious over the art.
Conclusion
Claims 8, 9 and 11 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMY M BUNKER whose telephone number is (313) 446-4833. The examiner can normally be reached on Monday-Friday (6am-2:30pm).
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Heather Calamita can be reached on (571) 272-2876. The fax phone number for the organization where this application or proceeding is assigned is (571) 273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/AMY M BUNKER/Primary Examiner, Art Unit 1684
Prosecution Insights