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 .
Priority
Receipt is acknowledged of certified copies of papers for application 202010467313.5, filed 5/28/20 in China, as required by 37 CFR 1.55.
Acknowledgment is made of applicant's claim for additional foreign priority based on application 202010468262.6 filed 5/28/20 in China, and international applications PCT/CN2020/120070 and PCT/CN2020/120071. It is noted, however, that certified copies of these applications have not been filed with the instant application as required by 37 CFR 1.55.
Election/Restrictions
Applicant’s election of species (1) combination of antibodies for CK-17, GATA-3, and hTERT (2) Papanicolaou stain (3) urothelial carcinoma (4) immunotherapy and (5) combination of antibodies against CK-17, GATA-3, and hTERT, in the reply filed on 1/9/26 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claim Status
The claim set filed 1/9/25 is acknowledged. Claims 2-54 are cancelled. Claims 1 and 55-73 are pending.
Claim 67 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 1/9/26.
Claims 1, 55-66, and 68-73 are currently under consideration for patentability under 37 CFR 1.104.
Information Disclosure Statement
The information disclosure statements filed on 11/21/22, 6/1/23, 1/3/24, and 4/15/24 have been considered. Signed copies are enclosed.
Notably, the disclosure statement filed lists a Search Report. The listing of the references cited in a Search Report itself is not considered to be an information disclosure statement (IDS) complying with 37 CFR 1.98. 37 CFR 1.98(a)(2) requires a legible copy of: (1) each foreign patent; (2) each publication or that portion which caused it to be listed; (3) for each cited pending U.S. application, the application specification including claims, and any drawing of the application, or that portion of the application which caused it to be listed including any claims directed to that portion, unless the cited pending U.S. application is stored in the Image File Wrapper (IFW) system; and (4) all other information, or that portion which caused it to be listed. In addition, each IDS must include a list of all patents, publications, applications, or other information submitted for consideration by the Office (see 37 CFR 1.98(a)(1) and (b)), and MPEP § 609.04(a), subsection I. states, "the list ... must be submitted on a separate paper." Therefore, the references cited in the Search Report have not been considered. Applicant is advised that the date of submission of any item of information or any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the IDS, including all "statement" requirements of 37 CFR 1.97(e). See MPEP § 609.05(a).
Note: If copies of the individual references cited on the Search Report are also cited separately on the IDS (and these references have not been lined-through) they have been considered.
Claim Objections
Claim 58 is objected to because of the following informalities: the claim contains a number of initialisms, acronyms, and/or abbreviations that should be spelled out upon first occurrence. Appropriate correction is required.
Claim Rejections - 35 USC § 112(a)
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, 55-66, and 68-73 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains 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, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention.”
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the Applicants were in possession of the claimed genus.
The instant claims are drawn to a method of detecting bladder cancer in a patient, comprising isolating urinary exfoliated cells from a patient and fixing the urinary cells then staining the cells and assessing the exfoliated cells to detect bladder cancer in a patient. The dependent claims further disclose centrifugation to isolate the exfoliated cells, the types of stains, and a list of possible biomarkers that are useful for detecting the bladder cancer.
The instant claims and specification do not adequately describe the steps necessary to detect bladder cancer. The method requires a specific function (i.e. detection of bladder cancer) but does not provide adequate description of the correlating structure (i.e. steps). The instant specification does not identify steps, thresholds, or specific combinations of biomarkers that could distinguish bladder cancer from other types of cancer. The claim therefore requires the specific function of detecting bladder cancer, but does not provide guidance regarding which combinations of limitations can produce the required function. Therefore, the specification provides insufficient written description to support the genus encompassed by the claim. Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that
"applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404. 1405 held that:
...To fulfill the written description requirement, a patent specification must describe an invention and does so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines Inc. , 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli , 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (" [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2datl966.
The skilled artisan cannot envision the steps, specific assay methods and specific measurement thresholds that are required to establish specific status outcomes. In general, the art regarding establishing biomarkers is unpredictable. Waiker et al (J Am Soc Nephrol. 2012 January; 23(1): 13–21) teach that although diagnostic tests are judged based on their ability to classify individuals according to disease status, the actual disease status is often not known with certainty in clinical medicine. As taught by Brooks (Genome Res. 2012. 22: 183-187), to be effective, a cancer screening strategy must detect malignant cells that are destined to grow, metastasize, and cause death. Unfortunately, little is known about the steps that lead transformed cells to become malignant and ultimately lethal, and this has major implications for biomarker performance. Cancers are complex tissues composed of many cell types. It is possible (and likely) that features of the host, such as the innate immune response to the malignancy, interactions of the malignant cells with the surrounding stroma, or stochastic factors that are not captured by any biomarker, are important in the progression of early lesions. Biomarkers developed against the bulk mass of the tumor could miss the attributes of the stem cells that ultimately determine the clinical course of a malignancy. In addition, many biomarkers fail because most malignancies display genomic instability and require multiple genetic hits to become metastatic. Measurement of a biomarker at a particular time might not predict acquisition of those future genetic alterations that are the product of this underlying genomic instability (See Brooks page 184). Brooks also teaches that genetic and histologic changes that occur with aging further complicate cancer detection strategies. Autopsy studies show histologically identifiable cancer precursor lesions (dysplasias and frank neoplasias) in a high proportion of the population and in many organ sites. This leads to a fundamental problem in cancer detection: If a biomarker is able to detect these initiated lesions of which only a fraction will progress, how does one sort out which lesions need to be treated and which can be safely ignored? Focusing on mutations or structural alterations within the malignant cells alone may be of limited utility in predicting biological and clinical behavior. Further, measurement of a biomarker at a particular time might not predict acquisition of those future genetic alterations that are the product of underlying genomic instability (see page 184). This is especially relevant, given that discovery based genomic studies have relied on samples of convenience, including tissue samples that have been banked from surgeries on individuals with relatively advanced disease in which the number of genomic changes is extraordinary. These changes make it difficult to identify critical early changes that could be used as diagnostic biomarkers (see page 185). Further, Waiker et al indicate that the threshold established for any given biomarker to describe any particular disease is critical for establishing the accuracy of the biomarker to predict disease (see page 8). The disclosure fails to resolve the specific methods, the specific thresholds, or the correlation of ghrelin with any specific disease state. Because the genus may be so highly variant, the examples provided, as well as the generic terms of “risk of progression” “risk of recurrent non-invasive disease" and “reduced level compared to control” is insufficient to describe the genus, even when considered in light of the general knowledge in the art.
Furthermore, the specification does not adequately describe the steps that are necessary to diagnose bladder cancer, or to distinguish bladder cancer from other types of cancer. For example, detection of S100P can be used to detect head and neck squamous cancer using urine samples (see e.g. Kuriakose et al (WO 2019/171110 A1; filed 3/4/18; published 9/12/19; claims 4 and 5 and paragraph [0038]-[0039]). Similarly, Tang et al (WO 2016/033103 A1; filed 8/25/15; published 3/3/16) teaches methods for screening a subject for cancer comprising detecting circulating tumor cells in a biological subject, wherein the cancer can be selected from several types such as carcinoma, sarcoma, neuroblastoma, melanoma, or other solid tumors (see e.g. claim 1-4). One measure of circulating tumor cells is the degree of PD-L1 expression (see e.g. claims 43-45). The markers can be detected using urine samples (see e.g. paragraph [0144]). These and other references suggest that the biomarkers identified in the instant claims and instant specification are not specific for any one type of cancer, and without further description of the steps, thresholds, and marker combinations, one of skill in the art would not be able to “immediately envisage” the claimed method for distinguishing bladder cancer from other types of cancers, or different types of bladder cancers from each other. .
Adequate written description requires more than a mere statement that is part of the invention. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. v. Chungai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. In Fiddes v. Baird, 30 USPQ2d 1481, 1483, claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
The University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404, 1405 held that: …To fulfill the written description requirement, a patent specification must describe an invention and does so in sufficient detail that one skilled in the art can clearly conclude that “the inventor invented the claimed invention.” Lockwood v. American Airlines Inc. 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) ("[T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus an Applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2dat1966.
MPEP § 2163.02 states, “[a]n objective standard for determining compliance with the written description requirement is, 'does the description clearly allow person of ordinary skill in the art to recognize that he or she invented what is claimed’”. The courts have decided: the purpose of the "written description" requirement is broader than to merely explain how to "make and use"; the Applicant must convey with reasonable clarity to those skilled in the art, that as of the filing date sought, he or she was in possession of the invention. The invention is for purposes of the “written description” inquiry, whatever is now claimed. See Vas-Cath, Inc v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Federal Circuit, 1991).
Furthermore, the written description provision of 35 USC §112 is severable from its enablement provision; and adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993). And Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. Moreover, an adequate written description of the claimed invention must include sufficient description of at least a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics sufficient to show that Applicant was in possession of the claimed genus. However, factual evidence of an actual reduction to practice has not been disclosed by Applicant in the specification; nor has Applicant shown the invention was “ready for patenting” by disclosure of drawings or structural chemical formulas that show that the invention was complete; nor has the Applicant described distinguishing identifying characteristics sufficient to show that Applicant were in possession of the claimed invention at the time the application was filed.
Therefore for all these reasons the specification lacks adequate written description, and one of skill in the art cannot reasonably conclude that Applicant had possession of the claimed invention at the time the instant application was filed.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 55-66, and 68-73 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites “thereby detecting bladder cancer” without setting forth steps for correlating any outcome with assessment of the cell characteristics. Without steps to diagnose the bladder cancer, the method steps are indefinite.
Claim 60 contains the trademark/trade name “Diff-Quik”. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe a type of cytomorphologic stain and, accordingly, the identification/description is indefinite.
Claim 60 recites “or a derivative or modification thereof”. The terms “derivative” and “modification” are not defined by the instant specification. When given their general meaning, the terms overlap in scope, and are possibly redundant. It is unclear what changes to the stains would fall in each category.
Claim 62 requires identifying “percentage of biomarker positive cells among bladder cancer cells.” The phrase appears to indicate that the bladder cancer has already been diagnosed, but the claims are directed to a method of detection of the cancer. It is impossible for a patient to be both undiagnosed and diagnosed at the same time. Further, it is unclear if additional steps are needed to separately diagnose the bladder cancer in addition to the claimed method.
The term “high risk” in claim 70 is a relative term which renders the claim indefinite. The term “high” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Claim 71 recites the limitation "the antibodies or binding fragments thereof". There is insufficient antecedent basis for this limitation in the claim.
Claim 71 recites “wherein any one or more of the antibodies or binding fragments thereof set forth in Figure 3 are utilized”. It is unclear what limitations are required by the term “utilized.” For example, it is unclear which “uses” are encompassed by the “utilization.”
Regarding claim 71, the claim references Figure 3 from the specification. Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table “is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience.” Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993)". See MPEP2173.05(s).”
Claim 71 recites Figure 3 to incorporate the antibodies listed in the figure. However these antibodies are listed by arbitrary clone names. These clone names do not identify or describe the antibodies associated with the clone name. Therefore the terms are indefinite.
In claim 72, the phrase “comprising nuclear features, shape or size of the nuclei or nucleoli” renders the claim indefinite. It is unclear if the terms “nuclear features” and “shape or size of the nuclei or nucleoli are alternatives or describing the same characteristics. A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 72 recites the broad recitation “nuclear features”, and the claim also recites “shape or size of the nuclei or nucleoli” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Regarding claim 72 and 73, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 73 recites the broad recitation of ranges of pore sizes, and the claim also recites species of pore sizes which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claims depending from the rejected claims do not remedy the deficiency and therefore are also rejected.
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, 55-66, and 69-73 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. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the additional elements, which are recited at a high level of generality, provide conventional assays and samples that do not add meaningful limits to practicing the law of nature and abstract idea.
The Supreme Court in Mayo laid out a framework for determining whether an applicant is seeking to patent a judicial exception itself, or a patent-eligible application of the judicial exception. See Alice Corp., 573 U.S. at 217-18, 110 USPQ2d at 1981 (citing Mayo, 566 U.S. 66, 101 USPQ2d 1961). See MPEP 2106.
The first step of the analysis asks whether the claimed invention is directed to a statutory category of invention. The instant claims recite a method of detecting bladder cancer in a patient by assessing urinary exfoliated cells after staining with multiple different stains. The claim is directed to a method, which is a statutory category of invention.
Second, the claimed invention also must qualify as patent-eligible subject matter, i.e., the claim must not be directed to a judicial exception unless the claim as a whole includes additional limitations amounting to significantly more than the exception (see MPEP 2106). Based upon an analysis with respect to the claim as a whole, the instant claims are determined to be directed to a law of nature/natural principle and an abstract idea. The relationship between the recited biomarkers and presence of a disease such as bladder cancer is a natural principle, which is a judicial exception. This method describes correlation of a particular biomarker with a particular natural disease state, which is comparable to concepts identified by the Supreme Court in Mayo. (see Mayo 101 USPQ2d at 1966). The use of the biomarkers and correlation with disease could be performed by a human using mental steps or basic critical thinking, which are types of activities that have been found by the courts to represent abstract ideas (e.g., the mental comparison in Ambry Genetics, or the diagnosing an abnormal condition by performing clinical tests and thinking about the results in Grams).
Third, a claim that is directed to a natural principle and/or abstract idea must also include additional elements or steps to show that the inventor has practically applied, or added something significant to, the natural principle itself. See Mayo 101 USPQ2d at 1966. Adding steps to a natural biological process that only recite well-understood, routine, conventional activity previously engaged in by researchers in the field would not be sufficient. See id. At 1966, 1970. The claims identifies sample types (e.g. urinary exfoliated cells) for testing, subjects to be tested, and well-known assays for determining protein product expression levels. The identification of sample types and subjects from which the samples are to be collected is routine in the art of medical testing. As stated in MPEP 2106.05(d), the courts have recognized the following laboratory techniques as well-understood, routine, conventional activity in the life science arts when they are claimed in a merely generic manner (e.g., at a high level of generality) or as insignificant extra-solution activity. Determining the level of a biomarker in blood by any means has been determined as one of the well-understood, routine, conventional activity: see 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). Regarding the assays to detect protein expression products, the assays claimed are routine in the art for detecting proteins and cells. This is acknowledged by the instant specification, which calls the cytomorphologic staining “routine” (see paragraph [0104]) and indicates that “Urine cytology…is routinely used in clinical practice as a noninvasive test for bladder cancer.” Therefore, the additional features of the claims (i.e., measuring the level of the recited biomarkers, and identifying the source of the sample for screening) do not ensure that the claims amount to significantly more than the natural principle itself. The claims use conventional means to observe a natural correlation and therefore the steps of the claimed methods are not sufficient to transform unpatentable natural correlations into patentable applications of those regularities. This is also supported by the findings of the in Ariosa Diagnostics, Inc. v. Sequenom, Inc., 115 USPQ2d 1152 (Fed. Cir. 2015), wherein the Federal Circuit held that claims that measure biological substances using methods that are routine and conventional do not amount to more than reliance on a correlation that is a law of nature for patentability.
The question of whether identification of the patient population amounts to significantly more than the judicial exception is addressed in Mayo Collaborative Serv. v. Prometheus Labs., Inc., 566 U.S. _, 132 S. Ct. 1289, 1293-94, 101 USPQ2d 1961, 1965-66 (2012) (citing Diehr, 450 U.S. at 187, 209 USPQ at 7), when the Supreme Court determined that process claims reciting a correlation may inhibit further discovery by improperly tying up future use of laws of nature, even though the laws of nature at issue are narrow laws that may have limited applications. After measurement of the correlation, the claims can tie up a doctor's subsequent treatment decisions, whether treatment does or does not change in light of inference the doctor has drawn using disclosed correlations, since the claims threaten to inhibit development of more refined treatment recommendations that combine the patentee's correlations with later discovered features, and since the correlation step of the claims is set forth in highly general language covering all processes that make use of the correlation. Further, the steps simply refer to a relevant patient population, which is a pre-existing audience; doctors wish to determine whether a particular patient has a disease, or if the disease has/has not progressed. The claims inform a relevant audience about certain laws of nature; and additional steps consist of well understood, routine, conventional activity already engaged in by the scientific community, and those steps, when viewed as a whole, add nothing significant beyond the sum of the parts taken separately. Even though the laws of nature at issue are narrow laws that may have limited applications, the claim does not amount to significantly more than the natural law itself.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1, 55-65, 69-70, and 73 is/are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by Shroyer et al (WO 2018/027091 A1; filed 8/4/17; published 2/8/18).
Claim 1 is directed to a method of detecting bladder cancer in a patient, comprising: isolating urinary exfoliated cells from the patient; fixing the urinary exfoliated cells in an aqueous cell suspension; staining the urinary exfoliated cells with a liquid-based immunocytochemistry or chromogenic in-situ hybridization stain, or both; staining the urinary exfoliated cells with a diagnostic cytomorphologic stain; assessing the urinary exfoliated cells as comprising bladder cancer cells by the immunocytochemistry or chromogenic in-situ hybridization stain, or both, and the diagnostic cytomorphologic stain; thereby detecting bladder cancer in the patient.
Claim 55 is directed to the method of claim 1, wherein the urinary exfoliated cells are urinary sediment cells isolated from the urine sample by centrifugation.
Claim 56 is directed to the method of claim 1, wherein the immunocytochemistry or chromogenic in-situ hybridization stain, or both, is performed in an aqueous cell suspension.
Claim 57 is directed to the method of claim 56, wherein the immunocytochemistry or chromogenic in-situ hybridization stain, or both, comprises labeling one or more bladder cancer specific biomarkers.
Claim 58 is directed to the method of claim 57, wherein the one or more bladder cancer specific biomarkers are selected from the group consisting of S100P, p63, M344, LDQ10, 19A211, GATA-3, Ki-67, p16, Her-2, PD-L1, CTLA4, CK-17, CK-20, nmp-22, bladder tumor antigen (BTA), hTERT, and mini-chromosome maintenance protein 5 (MCM5).
Claim 59 is directed to the method of claim 1, wherein the diagnostic cytomorphologic stain is performed either: a) in an aqueous cell suspension; or b) after mounting the urinary exfoliated cells onto a solid substrate.
Claim 60 is directed to the method of claim 59, wherein the diagnostic cytomorphologic stain comprises Diff-Quik stain, Papanicolaou stain, Wright-Giemsa stain, hematoxylin/eosin stain, or a derivative or modification thereof.
Claim 61 is directed to the method of claim 59, wherein the solid substrate is a microscope slide.
Claim 62 is directed to the method of claim 1, wherein the assessing step includes counting the numbers of total bladder cancer cells, or percentage of biomarker positive cells among bladder cancer cells, or both.
Claim 63 is directed to the method of claim 62, wherein the bladder cancer cells comprise one or more bladder cancer specific biomarkers selected from the group consisting of S100P, p63, M344, LDQ10, 19A211, GATA-3, Ki-67, p16, Her-2, PD-L1, CTLA4, CK-17, CK- 20, nmp-22, bladder tumor antigen (BTA), hTERT, and mini-chromosome maintenance protein 5 (MCM5).
Claim 64 is directed to the method of claim 1, wherein the bladder cancer is urothelial carcinoma, squamous cell carcinoma, adenocarcinoma, small cell carcinoma, sarcoma, or any combination thereof.
Claim 65 is directed to the method of claim 1, further comprising treating the patient for bladder cancer.
Claim 66 is directed to the method of claim 65, wherein treating the patient for bladder cancer comprises surgery, chemotherapy, immunotherapy, targeted therapy, or radiation therapy, or any combination thereof.
Claim 67 is directed to the method of claim 66, wherein the chemotherapy comprises administration of cisplatin, carboplatin, fluorouracil, mitomycin, gemcitabine, methotrexate, vinblastine, doxorubicin, erdafitinib, afatinib, docetaxel, or paclitaxel, or any combination thereof.
Claim 68 is directed to the method of claim 66, wherein the immunotherapy comprises administration of Bacillus Calmette-Guerin (BCG), atezolizumab, avelumab, durvalumab, enfortumab, nivolumab, ipilimumab, trastuzumab, disitamab, PRS-343, or pembrolizumab, or any combination thereof.
Claim 69 is directed to the method of claim 65, wherein the patient is a human.
Claim 70 is directed to the method of claim 1, wherein the patient is selected to provide urinary exfoliated cells based on presentation of clinical symptoms of bladder cancer and/or being part of a population at high risk of developing bladder cancer.
Claim 71 is directed to the method of claim 1, wherein any one or more of the antibodies or binding fragments thereof set forth in Figure 3 are utilized.
Claim 72 is directed to the method of claim 1, wherein assessing the urinary exfoliated cells by the diagnostic cytomorphologic stain comprises assessing characteristics of the urinary exfoliated cells comprising nuclear features, shape or size of the nuclei or nucleoli; the density of chromatin; cytoplasmic elements such as mucins, fat droplets or neurosecretory granules; or cell membrane features such as membrane grooves, projections, or vacuoles.
Claim 73 is directed to the method of claim 1, wherein staining the urinary exfoliated cells with the liquid-based immunocytochemistry or chromogenic in-situ hybridization stain, and/or staining the urinary exfoliated cells with the diagnostic cytomorphologic stain comprises centrifugation or use of one or more inserts or transwells, wherein the one or more inserts or transwells comprise a porous membrane that permits aqueous solution to pass but retains the urinary exfoliated cells, such as a porous membrane having a pore size of 1, 2, 3, 4, 5, 6, 7, or 8pm or having a pore size within a range defined by any two of the aforementioned pore sizes and, optionally, wherein the one or more inserts or transwells further comprise a flange, protrusion, tab, or handle.
Regarding the limitations of instant claim 1, Shroyer teaches measurement of cytokeratin 17 through detection of K17 protein in protein in a sample (see e.g. abstract and paragraph [0009], and claims 1-17, 26-41). The method can comprise measuring K17 in bladder cells through binding of an antibody to K17 protein in the sample (see e.g. paragraph [0009]). The levels of K17 are used to detect that the subject has bladder cancer, when the K17 levels are above a controls sample (see e.g. paragraph [0009]). The sample can be urine that contains bladder cells, and the method can detect urothelial carcinoma (see e.g. paragraph [0009]). The cells can be contacted with the anti-K17 antibody in suspension, after being suspended in phosphate buffered solution (see e.g. paragraph [0053]). The binding of the anti-K17 protein can be detected with a detectable marker (see e.g. paragraph [0053]). The samples can also be counterstained with hematoxylin and placed on slides (see e.g. paragraph [0044]). The urine sample is prepared by fixing the cells and then isolating the fixed cells by centrifugations (see e.g. paragraph [0053], and claims 1-17, 26-41).
Regarding the limitations of instant claims 55 and 73, Shroyer teaches that the urine sample is prepared by fixing the cells and then isolating the fixed cells by centrifugations (see e.g. paragraph [0053], and claims 1-17, 26-41).
Regarding the limitations of instant claim 56-59, 63, Shroyer teaches measurement of cytokeratin 17 through detection of K17 protein in protein in a sample (see e.g. abstract and paragraph [0009], and claims 1-17, 26-41). The method can comprise measuring K17 in bladder cells through binding of an antibody to K17 protein in the sample (see e.g. paragraph [0009]). The levels of K17 are used to detect that the subject has bladder cancer, when the K17 levels are above a controls sample (see e.g. paragraph [0009]). Shroyer teaches that the cells can be contacted with the anti-K17 antibody in suspension, after being suspended in phosphate buffered solution (see e.g. paragraph [0053]).
Regarding the limitations of instant claim 60-61, Shroyer teaches that the samples can also be counterstained with hematoxylin and placed on slides (see e.g. paragraph [0044]).
Regarding the limitations of instant claim 62, Shroyer teaches quantifying the number of stained cells and comparing to control to detect increase in K17(see e.g. paragraph [0047] and [0059]).
Regarding the limitations of instant claim 64, Shroyer teaches that the sample can be urine that contains bladder cells, and the method can detect urothelial carcinoma (see e.g. paragraph [0009]).
Regarding the limitations of instant claim 65, the method can be used to identify patients that should be treated (see e.g. paragraph [0005], [0029]).
Regarding the limitations of instant claim 69-70, the patient can be a human (see e.g. paragraph [0029]). The patient may have bladder cancer, indicating high risk of developing bladder cancer (see e.g. paragraph [0009]).
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, 55-66, 69-70, and 72-73 are rejected under 35 U.S.C. 103 as being unpatentable over Fradet et al (WO 98/12564; filed 9/5/97; published 3/26/98) in view of Sun (CN 102288471 A, published 2011-12-21).
Claim 1 is directed to a method of detecting bladder cancer in a patient, comprising: isolating urinary exfoliated cells from the patient; fixing the urinary exfoliated cells in an aqueous cell suspension; staining the urinary exfoliated cells with a liquid-based immunocytochemistry or chromogenic in-situ hybridization stain, or both; staining the urinary exfoliated cells with a diagnostic cytomorphologic stain; assessing the urinary exfoliated cells as comprising bladder cancer cells by the immunocytochemistry or chromogenic in-situ hybridization stain, or both, and the diagnostic cytomorphologic stain; thereby detecting bladder cancer in the patient.
Claim 55 is directed to the method of claim 1, wherein the urinary exfoliated cells are urinary sediment cells isolated from the urine sample by centrifugation.
Claim 56 is directed to the method of claim 1, wherein the immunocytochemistry or chromogenic in-situ hybridization stain, or both, is performed in an aqueous cell suspension.
Claim 57 is directed to the method of claim 56, wherein the immunocytochemistry or chromogenic in-situ hybridization stain, or both, comprises labeling one or more bladder cancer specific biomarkers.
Claim 58 is directed to the method of claim 57, wherein the one or more bladder cancer specific biomarkers are selected from the group consisting of S100P, p63, M344, LDQ10, 19A211, GATA-3, Ki-67, p16, Her-2, PD-L1, CTLA4, CK-17, CK-20, nmp-22, bladder tumor antigen (BTA), hTERT, and mini-chromosome maintenance protein 5 (MCM5).
Claim 59 is directed to the method of claim 1, wherein the diagnostic cytomorphologic stain is performed either: a) in an aqueous cell suspension; or b) after mounting the urinary exfoliated cells onto a solid substrate.
Claim 60 is directed to the method of claim 59, wherein the diagnostic cytomorphologic stain comprises Diff-Quik stain, Papanicolaou stain, Wright-Giemsa stain, hematoxylin/eosin stain, or a derivative or modification thereof.
Claim 61 is directed to the method of claim 59, wherein the solid substrate is a microscope slide.
Claim 62 is directed to the method of claim 1, wherein the assessing step includes counting the numbers of total bladder cancer cells, or percentage of biomarker positive cells among bladder cancer cells, or both.
Claim 63 is directed to the method of claim 62, wherein the bladder cancer cells comprise one or more bladder cancer specific biomarkers selected from the group consisting of S100P, p63, M344, LDQ10, 19A211, GATA-3, Ki-67, p16, Her-2, PD-L1, CTLA4, CK-17, CK- 20, nmp-22, bladder tumor antigen (BTA), hTERT, and mini-chromosome maintenance protein 5 (MCM5).
Claim 64 is directed to the method of claim 1, wherein the bladder cancer is urothelial carcinoma, squamous cell carcinoma, adenocarcinoma, small cell carcinoma, sarcoma, or any combination thereof.
Claim 65 is directed to the method of claim 1, further comprising treating the patient for bladder cancer.
Claim 66 is directed to the method of claim 65, wherein treating the patient for bladder cancer comprises surgery, chemotherapy, immunotherapy, targeted therapy, or radiation therapy, or any combination thereof.
Claim 67 is directed to the method of claim 66, wherein the chemotherapy comprises administration of cisplatin, carboplatin, fluorouracil, mitomycin, gemcitabine, methotrexate, vinblastine, doxorubicin, erdafitinib, afatinib, docetaxel, or paclitaxel, or any combination thereof.
Claim 68 is directed to the method of claim 66, wherein the immunotherapy comprises administration of Bacillus Calmette-Guerin (BCG), atezolizumab, avelumab, durvalumab, enfortumab, nivolumab, ipilimumab, trastuzumab, disitamab, PRS-343, or pembrolizumab, or any combination thereof.
Claim 69 is directed to the method of claim 65, wherein the patient is a human.
Claim 70 is directed to the method of claim 1, wherein the patient is selected to provide urinary exfoliated cells based on presentation of clinical symptoms of bladder cancer and/or being part of a population at high risk of developing bladder cancer.
Claim 71 is directed to the method of claim 1, wherein any one or more of the antibodies or binding fragments thereof set forth in Figure 3 are utilized.
Claim 72 is directed to the method of claim 1, wherein assessing the urinary exfoliated cells by the diagnostic cytomorphologic stain comprises assessing characteristics of the urinary exfoliated cells comprising nuclear features, shape or size of the nuclei or nucleoli; the density of chromatin; cytoplasmic elements such as mucins, fat droplets or neurosecretory granules; or cell membrane features such as membrane grooves, projections, or vacuoles.
Claim 73 is directed to the method of claim 1, wherein staining the urinary exfoliated cells with the liquid-based immunocytochemistry or chromogenic in-situ hybridization stain, and/or staining the urinary exfoliated cells with the diagnostic cytomorphologic stain comprises centrifugation or use of one or more inserts or transwells, wherein the one or more inserts or transwells comprise a porous membrane that permits aqueous solution to pass but retains the urinary exfoliated cells, such as a porous membrane having a pore size of 1, 2, 3, 4, 5, 6, 7, or 8pm or having a pore size within a range defined by any two of the aforementioned pore sizes and, optionally, wherein the one or more inserts or transwells further comprise a flange, protrusion, tab, or handle.
Fradet teaches a non-invasive method for detecting bladder cancer comprising contacting shedded cells from the bladder, fixing said cells, reacting the cells with an immunological composition comprising mabs m344, 19A211, and LDQ10 for a sufficient time to obtain decorated cells, performing a combination of immunocytological and classical cytological analyses on decorated cells, and assessing the absence or presence of bladder cancer (see e.g. Fradet claim 1). The detection of the antibodies can be through fluorophore tags (see e.g. page 55). The M344 antigen has been described for bladder cancer (see e.g. page 4). The samples can contain voided urine samples(see e.g. page 26), which can include a sample with shedded sediment cells from the bladder (see e.g. page 10). . The method comprises both immunological assay and routine cytology in the same cell preparation (see e.g. page 10), and the cells can be fixed then blotted on microscope slides to submit them to a modified Papanicolaou procedure (see e.g. page 10). The Papanicolaou stain can be carried out on a microscope slide (see e.g. page 26). The cells that were positive for the biomarkers can be counted to produce a percentage of positive cells (see e.g. page 23). The cancer type can be a carcinoma (see e.g. page 1-2). The patient can be treated with a single or multiple doses of an antibody (see e.g. page 18). The instant specification and claims references antibodies as immunotherapies (see e.g. instant specification paragraph [0148], for example), therefore the treatment of Fradet would meet the limitations of an immunotherapy. The patient can be a human (see e.g. Fradet abstract). The patients were suspected of having bladder cancer based on symptoms or history (see e.g. page 33). The assessment can include examining the cell membrane and vacuoles (see e.g. page 51). The method comprises a filtration see e.g. examples 8 and 9 on page 46-47).
Fradet does not teach a liquid based immunocytochemistry or chromogenic in situ hybridization stain in an aqueous cell suspension, or centrifugation of the urinary cells.
Sun teaches a multiple staining method for immunohistochemical staining and cell morphological staining comprising:
a) preparing cell suspension of the cell sample in a container;
b) performing immunohistochemical staining and/or nucleic acid chromogenic in situ hybridization staining on cells in the cell suspension in the container, comprising: i) adding a primary antibody that specifically binds to an antigen to the cell suspension to complete specific binding of the primary antibody to the antigen; ii) removing the unbound primary antibody, and then preparing cell suspension again, iii) adding a secondary antibody conjugated with a label to the cell suspension to specifically bind to the primary antibody; iv) removing the unbound secondary antibody conjugated with a label, and then preparing the cell suspension again,
c) performing cell morphological staining that can be used for pathological diagnosis on the cells in the container, and then smearing the multiply stained cells on a pathological slide, as in claim 1 (see, e.g., a multiple staining method for immunohistochemical staining and cell morphological staining – para. [0017]; step a) – para. [0017], step 1; step b), step i) – para. [0017], step 10; step b), step ii) – para. [0017], step 11; step b), step iii) – para. [0017], step 12; step b), step iv) – para. [0017], step 13; step c) – para. [0017], steps 14-15). It is understood that removing the supernatant in steps 2. and 4. of para. [0017] in Sun removes the unbound antibodies from the cell suspension.
Sun teaches the method wherein steps ii) and iv) are carried out by the following steps:
washing the cells
centrifuging the precipitated cells; and
discarding the supernatant,
as in claim 2 (see, e.g., para. [0017], steps 2-4).
Fradet and Sun are analogous to the field of the claimed invention because they are both in the field of cell staining. One of ordinary skill in the art before the effective filing date of the application would have found it obvious to incorporate the liquid-based immunocytochemistry of Sun into the method Fradet. An artisan would have been motivated to do so because Sun teaches that “for cell or the cell mass of suspension growth, when adopting cell climbing sheet to process, often can occur adherent be not in good state or on the slide two sides situations of growth simultaneously all, affect dyeing and the observation in later stage; In addition, in follow-up dyeing course, be attached to the cell of creep plate through after repeatedly rinsing, easily come off.” In other words, the staining of a non-adherent cell can be difficult and the use of liquid immunocytochemistry addresses this deficiency (see e.g. Sun, “Background Technology” on page 1). Further, the method of Sun changes the multiple step method of Fradet into a method with less steps that provides multiple staining, carrying out simultaneous staining of cell surface and core (see e.g. Sun, “Background Technology” on page 1). An artisan would have a reasonable expectation of success based on the given disclosures.
Further, it would have been obvious to one with ordinary skill in the art, at the time of the invention, to apply the principles of Sun to the method of Fradet as a known variation in the art. The Supreme Court set forth in KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), that if the scope and content of the prior art included a similar or analogous product, with differences between the claimed invention and prior art that were encompassed in known variation or in a principle known in the art, and one of ordinary skill in the art could have combined the elements as claimed by known methods, the claimed variation would have been predictable in to one of ordinary skill in the art. The method of Sun and Fradet are both staining methods that share many similarities and are variations within the same field of immunostaining and cytology. Thus, the combination of prior art references as combined provided a prima facie case of obviousness, absent convincing evidence to the contrary.
Claims 1, 55-66, 68-70, and 72-73 are rejected under 35 U.S.C. 103 as being unpatentable over Fradet et al (WO 98/12564; filed 9/5/97; published 3/26/98) in view of Sun (CN 102288471 A, published 2011-12-21) and further in view of Necchi et al (J Clin Oncol. 2018 Dec 1;36(34):3353-3360. Epub 2018 Oct 20).
Claim 1 is directed to a method of detecting bladder cancer in a patient, comprising: isolating urinary exfoliated cells from the patient; fixing the urinary exfoliated cells in an aqueous cell suspension; staining the urinary exfoliated cells with a liquid-based immunocytochemistry or chromogenic in-situ hybridization stain, or both; staining the urinary exfoliated cells with a diagnostic cytomorphologic stain; assessing the urinary exfoliated cells as comprising bladder cancer cells by the immunocytochemistry or chromogenic in-situ hybridization stain, or both, and the diagnostic cytomorphologic stain; thereby detecting bladder cancer in the patient.
Claim 55 is directed to the method of claim 1, wherein the urinary exfoliated cells are urinary sediment cells isolated from the urine sample by centrifugation.
Claim 56 is directed to the method of claim 1, wherein the immunocytochemistry or chromogenic in-situ hybridization stain, or both, is performed in an aqueous cell suspension.
Claim 57 is directed to the method of claim 56, wherein the immunocytochemistry or chromogenic in-situ hybridization stain, or both, comprises labeling one or more bladder cancer specific biomarkers.
Claim 58 is directed to the method of claim 57, wherein the one or more bladder cancer specific biomarkers are selected from the group consisting of S100P, p63, M344, LDQ10, 19A211, GATA-3, Ki-67, p16, Her-2, PD-L1, CTLA4, CK-17, CK-20, nmp-22, bladder tumor antigen (BTA), hTERT, and mini-chromosome maintenance protein 5 (MCM5).
Claim 59 is directed to the method of claim 1, wherein the diagnostic cytomorphologic stain is performed either: a) in an aqueous cell suspension; or b) after mounting the urinary exfoliated cells onto a solid substrate.
Claim 60 is directed to the method of claim 59, wherein the diagnostic cytomorphologic stain comprises Diff-Quik stain, Papanicolaou stain, Wright-Giemsa stain, hematoxylin/eosin stain, or a derivative or modification thereof.
Claim 61 is directed to the method of claim 59, wherein the solid substrate is a microscope slide.
Claim 62 is directed to the method of claim 1, wherein the assessing step includes counting the numbers of total bladder cancer cells, or percentage of biomarker positive cells among bladder cancer cells, or both.
Claim 63 is directed to the method of claim 62, wherein the bladder cancer cells comprise one or more bladder cancer specific biomarkers selected from the group consisting of S100P, p63, M344, LDQ10, 19A211, GATA-3, Ki-67, p16, Her-2, PD-L1, CTLA4, CK-17, CK- 20, nmp-22, bladder tumor antigen (BTA), hTERT, and mini-chromosome maintenance protein 5 (MCM5).
Claim 64 is directed to the method of claim 1, wherein the bladder cancer is urothelial carcinoma, squamous cell carcinoma, adenocarcinoma, small cell carcinoma, sarcoma, or any combination thereof.
Claim 65 is directed to the method of claim 1, further comprising treating the patient for bladder cancer.
Claim 66 is directed to the method of claim 65, wherein treating the patient for bladder cancer comprises surgery, chemotherapy, immunotherapy, targeted therapy, or radiation therapy, or any combination thereof.
Claim 67 is directed to the method of claim 66, wherein the chemotherapy comprises administration of cisplatin, carboplatin, fluorouracil, mitomycin, gemcitabine, methotrexate, vinblastine, doxorubicin, erdafitinib, afatinib, docetaxel, or paclitaxel, or any combination thereof.
Claim 68 is directed to the method of claim 66, wherein the immunotherapy comprises administration of Bacillus Calmette-Guerin (BCG), atezolizumab, avelumab, durvalumab, enfortumab, nivolumab, ipilimumab, trastuzumab, disitamab, PRS-343, or pembrolizumab, or any combination thereof.
Claim 69 is directed to the method of claim 65, wherein the patient is a human.
Claim 70 is directed to the method of claim 1, wherein the patient is selected to provide urinary exfoliated cells based on presentation of clinical symptoms of bladder cancer and/or being part of a population at high risk of developing bladder cancer.
Claim 71 is directed to the method of claim 1, wherein any one or more of the antibodies or binding fragments thereof set forth in Figure 3 are utilized.
Claim 72 is directed to the method of claim 1, wherein assessing the urinary exfoliated cells by the diagnostic cytomorphologic stain comprises assessing characteristics of the urinary exfoliated cells comprising nuclear features, shape or size of the nuclei or nucleoli; the density of chromatin; cytoplasmic elements such as mucins, fat droplets or neurosecretory granules; or cell membrane features such as membrane grooves, projections, or vacuoles.
Claim 73 is directed to the method of claim 1, wherein staining the urinary exfoliated cells with the liquid-based immunocytochemistry or chromogenic in-situ hybridization stain, and/or staining the urinary exfoliated cells with the diagnostic cytomorphologic stain comprises centrifugation or use of one or more inserts or transwells, wherein the one or more inserts or transwells comprise a porous membrane that permits aqueous solution to pass but retains the urinary exfoliated cells, such as a porous membrane having a pore size of 1, 2, 3, 4, 5, 6, 7, or 8pm or having a pore size within a range defined by any two of the aforementioned pore sizes and, optionally, wherein the one or more inserts or transwells further comprise a flange, protrusion, tab, or handle.
Fradet teaches a non-invasive method for detecting bladder cancer comprising contacting shedded cells from the bladder, fixing said cells, reacting the cells with an immunological composition comprising mabs m344, 19A211, and LDQ10 for a sufficient time to obtain decorated cells, performing a combination of immunocytological and classical cytological analyses on decorated cells, and assessing the absence or presence of bladder cancer (see e.g. Fradet claim 1). The detection of the antibodies can be through fluorophore tags (see e.g. page 55). The M344 antigen has been described for bladder cancer (see e.g. page 4). The samples can contain voided urine samples(see e.g. page 26), which can include a sample with shedded sediment cells from the bladder (see e.g. page 10). . The method comprises both immunological assay and routine cytology in the same cell preparation (see e.g. page 10), and the cells can be fixed then blotted on microscope slides to submit them to a modified Papanicolaou procedure (see e.g. page 10). The Papanicolaou stain can be carried out on a microscope slide (see e.g. page 26). The cells that were positive for the biomarkers can be counted to produce a percentage of positive cells (see e.g. page 23). The cancer type can be a carcinoma (see e.g. page 1-2). The patient can be treated with a single or multiple doses of an antibody (see e.g. page 18). The instant specification and claims references antibodies as immunotherapies (see e.g. instant specification paragraph [0148], for example), therefore the treatment of Fradet would meet the limitations of an immunotherapy. The patient can be a human (see e.g. Fradet abstract). The patients were suspected of having bladder cancer based on symptoms or history (see e.g. page 33). The assessment can include examining the cell membrane and vacuoles (see e.g. page 51). The method comprises a filtration see e.g. examples 8 and 9 on page 46-47).
Fradet does not teach a liquid based immunocytochemistry or chromogenic in situ hybridization stain in an aqueous cell suspension, or centrifugation of the urinary cells.
Sun teaches a multiple staining method for immunohistochemical staining and cell morphological staining comprising:
a) preparing cell suspension of the cell sample in a container;
b) performing immunohistochemical staining and/or nucleic acid chromogenic in situ hybridization staining on cells in the cell suspension in the container, comprising: i) adding a primary antibody that specifically binds to an antigen to the cell suspension to complete specific binding of the primary antibody to the antigen; ii) removing the unbound primary antibody, and then preparing cell suspension again, iii) adding a secondary antibody conjugated with a label to the cell suspension to specifically bind to the primary antibody; iv) removing the unbound secondary antibody conjugated with a label, and then preparing the cell suspension again,
c) performing cell morphological staining that can be used for pathological diagnosis on the cells in the container, and then smearing the multiply stained cells on a pathological slide, as in claim 1 (see, e.g., a multiple staining method for immunohistochemical staining and cell morphological staining – para. [0017]; step a) – para. [0017], step 1; step b), step i) – para. [0017], step 10; step b), step ii) – para. [0017], step 11; step b), step iii) – para. [0017], step 12; step b), step iv) – para. [0017], step 13; step c) – para. [0017], steps 14-15). It is understood that removing the supernatant in steps 2. and 4. of para. [0017] in Sun removes the unbound antibodies from the cell suspension.
Sun teaches the method wherein steps ii) and iv) are carried out by the following steps:
washing the cells
centrifuging the precipitated cells; and
discarding the supernatant,
as in claim 2 (see, e.g., para. [0017], steps 2-4).
Fradet and Sun are analogous to the field of the claimed invention because they are both in the field of cell staining. One of ordinary skill in the art before the effective filing date of the application would have found it obvious to incorporate the liquid-based immunocytochemistry of Sun into the method Fradet. An artisan would have been motivated to do so because Sun teaches that “for cell or the cell mass of suspension growth, when adopting cell climbing sheet to process, often can occur adherent be not in good state or on the slide two sides situations of growth simultaneously all, affect dyeing and the observation in later stage; In addition, in follow-up dyeing course, be attached to the cell of creep plate through after repeatedly rinsing, easily come off.” In other words, the staining of a non-adherent cell can be difficult and the use of liquid immunocytochemistry addresses this deficiency (see e.g. Sun, “Background Technology” on page 1). Further, the method of Sun changes the multiple step method of Fradet into a method with less steps that provides multiple staining, carrying out simultaneous dying of cell surface and core (see e.g. Sun, “Background Technology” on page 1). An artisan would have a reasonable expectation of success based on the given disclosures.
Further, it would have been obvious to one with ordinary skill in the art, at the time of the invention, to apply the principles of Sun to the method of Fradet as a known variation in the art. The Supreme Court set forth in KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), that if the scope and content of the prior art included a similar or analogous product, with differences between the claimed invention and prior art that were encompassed in known variation or in a principle known in the art, and one of ordinary skill in the art could have combined the elements as claimed by known methods, the claimed variation would have been predictable in to one of ordinary skill in the art. The method of Sun and Fradet are both staining methods that share many similarities and are variations within the same field of immunostaining and cytology. Thus, the combination of prior art references as combined provided a prima facie case of obviousness, absent convincing evidence to the contrary.
Neither Fradet nor Sun teach treatment of a patient with a therapy such as pembrolizumab as recited in instant claim 68.
Necchi et al teach treatment of urothelial carcinoma with pembrolizumab before radical cystectomy (see e.g. abstract). Prior to treatment, patients were tested for PD-L1 expression by immunohistochemistry (see e.g. page 3354, right column). Responses were significantly enriched in patients with expression of PD-L1 (see e.g. page 3357, left column).
It would have been obvious to one with ordinary skill in the art, at the time of the invention, to apply the testing and treatment of Necchi to the method of Fradet in view of Sun. Fradet and Sun describe methods for identifying biomarker expression, and optimized means for testing cells that are in suspension. Necchi identifies a specific combination of biomarker and treatment, wherein the biomarker predicts response to the treatment. The Supreme Court set forth in KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), that if the scope and content of the prior art included a similar or analogous product, with differences between the claimed invention and prior art that were encompassed in known variation or in a principle known in the art, and one of ordinary skill in the art could have combined the elements as claimed by known methods, the claimed variation would have been predictable in to one of ordinary skill in the art. Fradet, Sun and Necchi all use antibodies to stain bladder cancer cells to measure specific biomarker expression. It would be a known variation in the art to select specific biomarkers that correspond to treatment response for application to a patient through biomarker expression assays. The detection of PD-L1 expression in the assay of Fradet in view of Sun would not require alterations in components or function of the method. In fact, one of skill in the art would be motivated to apply a known biomarker for treatment response to a method providing superior staining for detection of bladder cancer. Thus, the combination of prior art references as combined provided a prima facie case of obviousness, absent convincing evidence to the contrary.
Claims 1, 55-66, and 69-73 are rejected under 35 U.S.C. 103 as being unpatentable over Fradet et al (WO 98/12564; filed 9/5/97; published 3/26/98) in view of Sun (CN 102288471 A, published 2011-12-21) and further in view of Oosterhuis et al (Cancer. 2000 Jun 1;88(11):2598-605).
Claim 1 is directed to a method of detecting bladder cancer in a patient, comprising: isolating urinary exfoliated cells from the patient; fixing the urinary exfoliated cells in an aqueous cell suspension; staining the urinary exfoliated cells with a liquid-based immunocytochemistry or chromogenic in-situ hybridization stain, or both; staining the urinary exfoliated cells with a diagnostic cytomorphologic stain; assessing the urinary exfoliated cells as comprising bladder cancer cells by the immunocytochemistry or chromogenic in-situ hybridization stain, or both, and the diagnostic cytomorphologic stain; thereby detecting bladder cancer in the patient.
Claim 55 is directed to the method of claim 1, wherein the urinary exfoliated cells are urinary sediment cells isolated from the urine sample by centrifugation.
Claim 56 is directed to the method of claim 1, wherein the immunocytochemistry or chromogenic in-situ hybridization stain, or both, is performed in an aqueous cell suspension.
Claim 57 is directed to the method of claim 56, wherein the immunocytochemistry or chromogenic in-situ hybridization stain, or both, comprises labeling one or more bladder cancer specific biomarkers.
Claim 58 is directed to the method of claim 57, wherein the one or more bladder cancer specific biomarkers are selected from the group consisting of S100P, p63, M344, LDQ10, 19A211, GATA-3, Ki-67, p16, Her-2, PD-L1, CTLA4, CK-17, CK-20, nmp-22, bladder tumor antigen (BTA), hTERT, and mini-chromosome maintenance protein 5 (MCM5).
Claim 59 is directed to the method of claim 1, wherein the diagnostic cytomorphologic stain is performed either: a) in an aqueous cell suspension; or b) after mounting the urinary exfoliated cells onto a solid substrate.
Claim 60 is directed to the method of claim 59, wherein the diagnostic cytomorphologic stain comprises Diff-Quik stain, Papanicolaou stain, Wright-Giemsa stain, hematoxylin/eosin stain, or a derivative or modification thereof.
Claim 61 is directed to the method of claim 59, wherein the solid substrate is a microscope slide.
Claim 62 is directed to the method of claim 1, wherein the assessing step includes counting the numbers of total bladder cancer cells, or percentage of biomarker positive cells among bladder cancer cells, or both.
Claim 63 is directed to the method of claim 62, wherein the bladder cancer cells comprise one or more bladder cancer specific biomarkers selected from the group consisting of S100P, p63, M344, LDQ10, 19A211, GATA-3, Ki-67, p16, Her-2, PD-L1, CTLA4, CK-17, CK- 20, nmp-22, bladder tumor antigen (BTA), hTERT, and mini-chromosome maintenance protein 5 (MCM5).
Claim 64 is directed to the method of claim 1, wherein the bladder cancer is urothelial carcinoma, squamous cell carcinoma, adenocarcinoma, small cell carcinoma, sarcoma, or any combination thereof.
Claim 65 is directed to the method of claim 1, further comprising treating the patient for bladder cancer.
Claim 66 is directed to the method of claim 65, wherein treating the patient for bladder cancer comprises surgery, chemotherapy, immunotherapy, targeted therapy, or radiation therapy, or any combination thereof.
Claim 67 is directed to the method of claim 66, wherein the chemotherapy comprises administration of cisplatin, carboplatin, fluorouracil, mitomycin, gemcitabine, methotrexate, vinblastine, doxorubicin, erdafitinib, afatinib, docetaxel, or paclitaxel, or any combination thereof.
Claim 68 is directed to the method of claim 66, wherein the immunotherapy comprises administration of Bacillus Calmette-Guerin (BCG), atezolizumab, avelumab, durvalumab, enfortumab, nivolumab, ipilimumab, trastuzumab, disitamab, PRS-343, or pembrolizumab, or any combination thereof.
Claim 69 is directed to the method of claim 65, wherein the patient is a human.
Claim 70 is directed to the method of claim 1, wherein the patient is selected to provide urinary exfoliated cells based on presentation of clinical symptoms of bladder cancer and/or being part of a population at high risk of developing bladder cancer.
Claim 71 is directed to the method of claim 1, wherein any one or more of the antibodies or binding fragments thereof set forth in Figure 3 are utilized.
Claim 72 is directed to the method of claim 1, wherein assessing the urinary exfoliated cells by the diagnostic cytomorphologic stain comprises assessing characteristics of the urinary exfoliated cells comprising nuclear features, shape or size of the nuclei or nucleoli; the density of chromatin; cytoplasmic elements such as mucins, fat droplets or neurosecretory granules; or cell membrane features such as membrane grooves, projections, or vacuoles.
Claim 73 is directed to the method of claim 1, wherein staining the urinary exfoliated cells with the liquid-based immunocytochemistry or chromogenic in-situ hybridization stain, and/or staining the urinary exfoliated cells with the diagnostic cytomorphologic stain comprises centrifugation or use of one or more inserts or transwells, wherein the one or more inserts or transwells comprise a porous membrane that permits aqueous solution to pass but retains the urinary exfoliated cells, such as a porous membrane having a pore size of 1, 2, 3, 4, 5, 6, 7, or 8pm or having a pore size within a range defined by any two of the aforementioned pore sizes and, optionally, wherein the one or more inserts or transwells further comprise a flange, protrusion, tab, or handle.
Fradet teaches a non-invasive method for detecting bladder cancer comprising contacting shedded cells from the bladder, fixing said cells, reacting the cells with an immunological composition comprising mabs m344, 19A211, and LDQ10 for a sufficient time to obtain decorated cells, performing a combination of immunocytological and classical cytological analyses on decorated cells, and assessing the absence or presence of bladder cancer (see e.g. Fradet claim 1). The detection of the antibodies can be through fluorophore tags (see e.g. page 55). The M344 antigen has been described for bladder cancer (see e.g. page 4). The samples can contain voided urine samples(see e.g. page 26), which can include a sample with shedded sediment cells from the bladder (see e.g. page 10). . The method comprises both immunological assay and routine cytology in the same cell preparation (see e.g. page 10), and the cells can be fixed then blotted on microscope slides to submit them to a modified Papanicolaou procedure (see e.g. page 10). The Papanicolaou stain can be carried out on a microscope slide (see e.g. page 26). The cells that were positive for the biomarkers can be counted to produce a percentage of positive cells (see e.g. page 23). The cancer type can be a carcinoma (see e.g. page 1-2). The patient can be treated with a single or multiple doses of an antibody (see e.g. page 18). The instant specification and claims references antibodies as immunotherapies (see e.g. instant specification paragraph [0148], for example), therefore the treatment of Fradet would meet the limitations of an immunotherapy. The patient can be a human (see e.g. Fradet abstract). The patients were suspected of having bladder cancer based on symptoms or history (see e.g. page 33). The assessment can include examining the cell membrane and vacuoles (see e.g. page 51). The method comprises a filtration see e.g. examples 8 and 9 on page 46-47).
Fradet does not teach a liquid based immunocytochemistry or chromogenic in situ hybridization stain in an aqueous cell suspension, or centrifugation of the urinary cells.
Sun teaches a multiple staining method for immunohistochemical staining and cell morphological staining comprising:
a) preparing cell suspension of the cell sample in a container;
b) performing immunohistochemical staining and/or nucleic acid chromogenic in situ hybridization staining on cells in the cell suspension in the container, comprising: i) adding a primary antibody that specifically binds to an antigen to the cell suspension to complete specific binding of the primary antibody to the antigen; ii) removing the unbound primary antibody, and then preparing cell suspension again, iii) adding a secondary antibody conjugated with a label to the cell suspension to specifically bind to the primary antibody; iv) removing the unbound secondary antibody conjugated with a label, and then preparing the cell suspension again,
c) performing cell morphological staining that can be used for pathological diagnosis on the cells in the container, and then smearing the multiply stained cells on a pathological slide, as in claim 1 (see, e.g., a multiple staining method for immunohistochemical staining and cell morphological staining – para. [0017]; step a) – para. [0017], step 1; step b), step i) – para. [0017], step 10; step b), step ii) – para. [0017], step 11; step b), step iii) – para. [0017], step 12; step b), step iv) – para. [0017], step 13; step c) – para. [0017], steps 14-15). It is understood that removing the supernatant in steps 2. and 4. of para. [0017] in Sun removes the unbound antibodies from the cell suspension.
Sun teaches the method wherein steps ii) and iv) are carried out by the following steps:
washing the cells
centrifuging the precipitated cells; and
discarding the supernatant,
as in claim 2 (see, e.g., para. [0017], steps 2-4).
Fradet and Sun are analogous to the field of the claimed invention because they are both in the field of cell staining. One of ordinary skill in the art before the effective filing date of the application would have found it obvious to incorporate the liquid-based immunocytochemistry of Sun into the method Fradet. An artisan would have been motivated to do so because Sun teaches that “for cell or the cell mass of suspension growth, when adopting cell climbing sheet to process, often can occur adherent be not in good state or on the slide two sides situations of growth simultaneously all, affect dyeing and the observation in later stage; In addition, in follow-up dyeing course, be attached to the cell of creep plate through after repeatedly rinsing, easily come off.” In other words, the staining of a non-adherent cell can be difficult and the use of liquid immunocytochemistry addresses this deficiency (see e.g. Sun, “Background Technology” on page 1). Further, the method of Sun changes the multiple step method of Fradet into a method with less steps that provides multiple staining, carrying out simultaneous dying of cell surface and core (see e.g. Sun, “Background Technology” on page 1). An artisan would have a reasonable expectation of success based on the given disclosures.
Further, it would have been obvious to one with ordinary skill in the art, at the time of the invention, to apply the principles of Sun to the method of Fradet as a known variation in the art. The Supreme Court set forth in KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), that if the scope and content of the prior art included a similar or analogous product, with differences between the claimed invention and prior art that were encompassed in known variation or in a principle known in the art, and one of ordinary skill in the art could have combined the elements as claimed by known methods, the claimed variation would have been predictable in to one of ordinary skill in the art. The method of Sun and Fradet are both staining methods that share many similarities and are variations within the same field of immunostaining and cytology. Thus, the combination of prior art references as combined provided a prima facie case of obviousness, absent convincing evidence to the contrary.
Neither Fradet nor Sun teach antibodies of Figure 3 as recited in instant claim 71.
Oosterhuis teaches an detection of transitional cell carcinoma of the bladder with MIB-1 using immunostaining (see e.g. abstract and page 2599, left column).
It would have been obvious to one with ordinary skill in the art, at the time of the invention, to apply the MIB-1 antibody to the method of Fradet in view of Sun. Fradet and Sun describe methods for identifying biomarker expression, and optimized means for testing cells that are in suspension. Oosterhuis identifies a specific biomarker for detecting bladder cancer. The Supreme Court set forth in KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), that if the scope and content of the prior art included a similar or analogous product, with differences between the claimed invention and prior art that were encompassed in known variation or in a principle known in the art, and one of ordinary skill in the art could have combined the elements as claimed by known methods, the claimed variation would have been predictable in to one of ordinary skill in the art. Fradet, Sun and Oosterhuis all use antibodies to stain bladder cancer cells to measure specific biomarker expression. It would be a known variation in the art to select specific biomarkers that correspond to detection of bladder cancer for application to a patient through biomarker expression assays. The detection of Ki-67 expression in the assay of Fradet in view of Sun would not require alterations in components or function of the method. In fact, one of skill in the art would be motivated to apply a known biomarker for detection of bladder cancer to a method providing superior staining for detection of bladder cancer. Thus, the combination of prior art references as combined provided a prima facie case of obviousness, absent convincing evidence to the contrary.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 55-66, 69-70, and 72-73 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of copending Application No. 17/928,039 (reference application) in view of Fradet et al (WO 98/12564; filed 9/5/97; published 3/26/98).
Although the claims at issue are not identical, they are not patentably distinct from each other.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 1 is directed to a method of detecting bladder cancer in a patient, comprising: isolating urinary exfoliated cells from the patient; fixing the urinary exfoliated cells in an aqueous cell suspension; staining the urinary exfoliated cells with a liquid-based immunocytochemistry or chromogenic in-situ hybridization stain, or both; staining the urinary exfoliated cells with a diagnostic cytomorphologic stain; assessing the urinary exfoliated cells as comprising bladder cancer cells by the immunocytochemistry or chromogenic in-situ hybridization stain, or both, and the diagnostic cytomorphologic stain; thereby detecting bladder cancer in the patient.
Claim 55 is directed to the method of claim 1, wherein the urinary exfoliated cells are urinary sediment cells isolated from the urine sample by centrifugation.
Claim 56 is directed to the method of claim 1, wherein the immunocytochemistry or chromogenic in-situ hybridization stain, or both, is performed in an aqueous cell suspension.
Claim 57 is directed to the method of claim 56, wherein the immunocytochemistry or chromogenic in-situ hybridization stain, or both, comprises labeling one or more bladder cancer specific biomarkers.
Claim 58 is directed to the method of claim 57, wherein the one or more bladder cancer specific biomarkers are selected from the group consisting of S100P, p63, M344, LDQ10, 19A211, GATA-3, Ki-67, p16, Her-2, PD-L1, CTLA4, CK-17, CK-20, nmp-22, bladder tumor antigen (BTA), hTERT, and mini-chromosome maintenance protein 5 (MCM5).
Claim 59 is directed to the method of claim 1, wherein the diagnostic cytomorphologic stain is performed either: a) in an aqueous cell suspension; or b) after mounting the urinary exfoliated cells onto a solid substrate.
Claim 60 is directed to the method of claim 59, wherein the diagnostic cytomorphologic stain comprises Diff-Quik stain, Papanicolaou stain, Wright-Giemsa stain, hematoxylin/eosin stain, or a derivative or modification thereof.
Claim 61 is directed to the method of claim 59, wherein the solid substrate is a microscope slide.
Claim 62 is directed to the method of claim 1, wherein the assessing step includes counting the numbers of total bladder cancer cells, or percentage of biomarker positive cells among bladder cancer cells, or both.
Claim 63 is directed to the method of claim 62, wherein the bladder cancer cells comprise one or more bladder cancer specific biomarkers selected from the group consisting of S100P, p63, M344, LDQ10, 19A211, GATA-3, Ki-67, p16, Her-2, PD-L1, CTLA4, CK-17, CK- 20, nmp-22, bladder tumor antigen (BTA), hTERT, and mini-chromosome maintenance protein 5 (MCM5).
Claim 64 is directed to the method of claim 1, wherein the bladder cancer is urothelial carcinoma, squamous cell carcinoma, adenocarcinoma, small cell carcinoma, sarcoma, or any combination thereof.
Claim 65 is directed to the method of claim 1, further comprising treating the patient for bladder cancer.
Claim 66 is directed to the method of claim 65, wherein treating the patient for bladder cancer comprises surgery, chemotherapy, immunotherapy, targeted therapy, or radiation therapy, or any combination thereof.
Claim 67 is directed to the method of claim 66, wherein the chemotherapy comprises administration of cisplatin, carboplatin, fluorouracil, mitomycin, gemcitabine, methotrexate, vinblastine, doxorubicin, erdafitinib, afatinib, docetaxel, or paclitaxel, or any combination thereof.
Claim 68 is directed to the method of claim 66, wherein the immunotherapy comprises administration of Bacillus Calmette-Guerin (BCG), atezolizumab, avelumab, durvalumab, enfortumab, nivolumab, ipilimumab, trastuzumab, disitamab, PRS-343, or pembrolizumab, or any combination thereof.
Claim 69 is directed to the method of claim 65, wherein the patient is a human.
Claim 70 is directed to the method of claim 1, wherein the patient is selected to provide urinary exfoliated cells based on presentation of clinical symptoms of bladder cancer and/or being part of a population at high risk of developing bladder cancer.
Claim 71 is directed to the method of claim 1, wherein any one or more of the antibodies or binding fragments thereof set forth in Figure 3 are utilized.
Claim 72 is directed to the method of claim 1, wherein assessing the urinary exfoliated cells by the diagnostic cytomorphologic stain comprises assessing characteristics of the urinary exfoliated cells comprising nuclear features, shape or size of the nuclei or nucleoli; the density of chromatin; cytoplasmic elements such as mucins, fat droplets or neurosecretory granules; or cell membrane features such as membrane grooves, projections, or vacuoles.
Claim 73 is directed to the method of claim 1, wherein staining the urinary exfoliated cells with the liquid-based immunocytochemistry or chromogenic in-situ hybridization stain, and/or staining the urinary exfoliated cells with the diagnostic cytomorphologic stain comprises centrifugation or use of one or more inserts or transwells, wherein the one or more inserts or transwells comprise a porous membrane that permits aqueous solution to pass but retains the urinary exfoliated cells, such as a porous membrane having a pore size of 1, 2, 3, 4, 5, 6, 7, or 8pm or having a pore size within a range defined by any two of the aforementioned pore sizes and, optionally, wherein the one or more inserts or transwells further comprise a flange, protrusion, tab, or handle.
The reference application is directed to a multiple staining method for making immunohistochemical staining and/or nucleic acid chromogenic in situ hybridization staining and cell morphological staining that can be used for pathological diagnosis in a cell sample comprising preparing a cell suspension of the cell sample in a container, performing immunohistochemical staining and/or nucleic acid chromogenic in situ hybridization staining on cells in a cell suspension comprising adding antibodies that bind to an antigen, removing unbound antibody, adding a secondary antibody conjugated with a probe, removing the unbound secondary antibody, adding a chromogenic substrate, removing the excess chromogenic substrate, performing morphogenic staining for pathological diagnosis, smearing the stains on a slide (see e.g. claim 1). The method can also include washing the cells, centrifuging the cells, and discarding the supernatant (see e.g. claim 2). The cell morphological staining can be the same type of staining as the instant claims, such as Diff-Quik staining (see e.g. claim 3). The sample can be urine (see e.g. claim 5). The staining can probe cell membrane, cytoplasm, and/or cell nucleus (see e.g. claim 6).
The reference application does not teach detection of bladder cancer or labeling with specific bladder cancer markers.
Fradet teaches a non-invasive method for detecting bladder cancer comprising contacting shedded cells from the bladder, fixing said cells, reacting the cells with an immunological composition comprising mabs m344, 19A211, and LDQ10 for a sufficient time to obtain decorated cells, performing a combination of immunocytological and classical cytological analyses on decorated cells, and assessing the absence or presence of bladder cancer (see e.g. Fradet claim 1). The detection of the antibodies can be through fluorophore tags (see e.g. page 55). The M344 antigen has been described for bladder cancer (see e.g. page 4). The samples can contain voided urine samples(see e.g. page 26), which can include a sample with shedded sediment cells from the bladder (see e.g. page 10). . The method comprises both immunological assay and routine cytology in the same cell preparation (see e.g. page 10), and the cells can be fixed then blotted on microscope slides to submit them to a modified Papanicolaou procedure (see e.g. page 10). The Papanicolaou stain can be carried out on a microscope slide (see e.g. page 26). The cells that were positive for the biomarkers can be counted to produce a percentage of positive cells (see e.g. page 23). The cancer type can be a carcinoma (see e.g. page 1-2). The patient can be treated with a single or multiple doses of an antibody (see e.g. page 18). The instant specification and claims references antibodies as immunotherapies (see e.g. instant specification paragraph [0148], for example), therefore the treatment of Fradet would meet the limitations of an immunotherapy. The patient can be a human (see e.g. Fradet abstract). The patients were suspected of having bladder cancer based on symptoms or history (see e.g. page 33). The assessment can include examining the cell membrane and vacuoles (see e.g. page 51). The method comprises a filtration see e.g. examples 8 and 9 on page 46-47).
It would have been obvious to one with ordinary skill in the art, at the time of the invention, to apply the principles of Fradet to the method of the reference patent as a known variation in the art. The Supreme Court set forth in KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), that if the scope and content of the prior art included a similar or analogous product, with differences between the claimed invention and prior art that were encompassed in known variation or in a principle known in the art, and one of ordinary skill in the art could have combined the elements as claimed by known methods, the claimed variation would have been predictable in to one of ordinary skill in the art. The method of the reference patent and Fradet are both staining methods that share many similarities and are variations within the same field of immunostaining and cytology. Thus, the combination of prior art references as combined provided a prima facie case of obviousness, absent convincing evidence to the contrary.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 55-66, 68-70, and 72-73 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of copending Application No. 17/928,039 (reference application) in view of Fradet et al (WO 98/12564; filed 9/5/97; published 3/26/98) and further in view of Necchi et al (J Clin Oncol. 2018 Dec 1;36(34):3353-3360. Epub 2018 Oct 20).
Although the claims at issue are not identical, they are not patentably distinct from each other.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 1 is directed to a method of detecting bladder cancer in a patient, comprising: isolating urinary exfoliated cells from the patient; fixing the urinary exfoliated cells in an aqueous cell suspension; staining the urinary exfoliated cells with a liquid-based immunocytochemistry or chromogenic in-situ hybridization stain, or both; staining the urinary exfoliated cells with a diagnostic cytomorphologic stain; assessing the urinary exfoliated cells as comprising bladder cancer cells by the immunocytochemistry or chromogenic in-situ hybridization stain, or both, and the diagnostic cytomorphologic stain; thereby detecting bladder cancer in the patient.
Claim 55 is directed to the method of claim 1, wherein the urinary exfoliated cells are urinary sediment cells isolated from the urine sample by centrifugation.
Claim 56 is directed to the method of claim 1, wherein the immunocytochemistry or chromogenic in-situ hybridization stain, or both, is performed in an aqueous cell suspension.
Claim 57 is directed to the method of claim 56, wherein the immunocytochemistry or chromogenic in-situ hybridization stain, or both, comprises labeling one or more bladder cancer specific biomarkers.
Claim 58 is directed to the method of claim 57, wherein the one or more bladder cancer specific biomarkers are selected from the group consisting of S100P, p63, M344, LDQ10, 19A211, GATA-3, Ki-67, p16, Her-2, PD-L1, CTLA4, CK-17, CK-20, nmp-22, bladder tumor antigen (BTA), hTERT, and mini-chromosome maintenance protein 5 (MCM5).
Claim 59 is directed to the method of claim 1, wherein the diagnostic cytomorphologic stain is performed either: a) in an aqueous cell suspension; or b) after mounting the urinary exfoliated cells onto a solid substrate.
Claim 60 is directed to the method of claim 59, wherein the diagnostic cytomorphologic stain comprises Diff-Quik stain, Papanicolaou stain, Wright-Giemsa stain, hematoxylin/eosin stain, or a derivative or modification thereof.
Claim 61 is directed to the method of claim 59, wherein the solid substrate is a microscope slide.
Claim 62 is directed to the method of claim 1, wherein the assessing step includes counting the numbers of total bladder cancer cells, or percentage of biomarker positive cells among bladder cancer cells, or both.
Claim 63 is directed to the method of claim 62, wherein the bladder cancer cells comprise one or more bladder cancer specific biomarkers selected from the group consisting of S100P, p63, M344, LDQ10, 19A211, GATA-3, Ki-67, p16, Her-2, PD-L1, CTLA4, CK-17, CK- 20, nmp-22, bladder tumor antigen (BTA), hTERT, and mini-chromosome maintenance protein 5 (MCM5).
Claim 64 is directed to the method of claim 1, wherein the bladder cancer is urothelial carcinoma, squamous cell carcinoma, adenocarcinoma, small cell carcinoma, sarcoma, or any combination thereof.
Claim 65 is directed to the method of claim 1, further comprising treating the patient for bladder cancer.
Claim 66 is directed to the method of claim 65, wherein treating the patient for bladder cancer comprises surgery, chemotherapy, immunotherapy, targeted therapy, or radiation therapy, or any combination thereof.
Claim 67 is directed to the method of claim 66, wherein the chemotherapy comprises administration of cisplatin, carboplatin, fluorouracil, mitomycin, gemcitabine, methotrexate, vinblastine, doxorubicin, erdafitinib, afatinib, docetaxel, or paclitaxel, or any combination thereof.
Claim 68 is directed to the method of claim 66, wherein the immunotherapy comprises administration of Bacillus Calmette-Guerin (BCG), atezolizumab, avelumab, durvalumab, enfortumab, nivolumab, ipilimumab, trastuzumab, disitamab, PRS-343, or pembrolizumab, or any combination thereof.
Claim 69 is directed to the method of claim 65, wherein the patient is a human.
Claim 70 is directed to the method of claim 1, wherein the patient is selected to provide urinary exfoliated cells based on presentation of clinical symptoms of bladder cancer and/or being part of a population at high risk of developing bladder cancer.
Claim 71 is directed to the method of claim 1, wherein any one or more of the antibodies or binding fragments thereof set forth in Figure 3 are utilized.
Claim 72 is directed to the method of claim 1, wherein assessing the urinary exfoliated cells by the diagnostic cytomorphologic stain comprises assessing characteristics of the urinary exfoliated cells comprising nuclear features, shape or size of the nuclei or nucleoli; the density of chromatin; cytoplasmic elements such as mucins, fat droplets or neurosecretory granules; or cell membrane features such as membrane grooves, projections, or vacuoles.
Claim 73 is directed to the method of claim 1, wherein staining the urinary exfoliated cells with the liquid-based immunocytochemistry or chromogenic in-situ hybridization stain, and/or staining the urinary exfoliated cells with the diagnostic cytomorphologic stain comprises centrifugation or use of one or more inserts or transwells, wherein the one or more inserts or transwells comprise a porous membrane that permits aqueous solution to pass but retains the urinary exfoliated cells, such as a porous membrane having a pore size of 1, 2, 3, 4, 5, 6, 7, or 8pm or having a pore size within a range defined by any two of the aforementioned pore sizes and, optionally, wherein the one or more inserts or transwells further comprise a flange, protrusion, tab, or handle.
The reference application is directed to a multiple staining method for making immunohistochemical staining and/or nucleic acid chromogenic in situ hybridization staining and cell morphological staining that can be used for pathological diagnosis in a cell sample comprising preparing a cell suspension of the cell sample in a container, performing immunohistochemical staining and/or nucleic acid chromogenic in situ hybridization staining on cells in a cell suspension comprising adding antibodies that bind to an antigen, removing unbound antibody, adding a secondary antibody conjugated with a probe, removing the unbound secondary antibody, adding a chromogenic substrate, removing the excess chromogenic substrate, performing morphogenic staining for pathological diagnosis, smearing the stains on a slide (see e.g. claim 1). The method can also include washing the cells, centrifuging the cells, and discarding the supernatant (see e.g. claim 2). The cell morphological staining can be the same type of staining as the instant claims, such as Diff-Quik staining (see e.g. claim 3). The sample can be urine (see e.g. claim 5). The staining can probe cell membrane, cytoplasm, and/or cell nucleus (see e.g. claim 6).
The reference application does not teach detection of bladder cancer or labeling with specific bladder cancer markers.
Fradet teaches a non-invasive method for detecting bladder cancer comprising contacting shedded cells from the bladder, fixing said cells, reacting the cells with an immunological composition comprising mabs m344, 19A211, and LDQ10 for a sufficient time to obtain decorated cells, performing a combination of immunocytological and classical cytological analyses on decorated cells, and assessing the absence or presence of bladder cancer (see e.g. Fradet claim 1). The detection of the antibodies can be through fluorophore tags (see e.g. page 55). The M344 antigen has been described for bladder cancer (see e.g. page 4). The samples can contain voided urine samples(see e.g. page 26), which can include a sample with shedded sediment cells from the bladder (see e.g. page 10). . The method comprises both immunological assay and routine cytology in the same cell preparation (see e.g. page 10), and the cells can be fixed then blotted on microscope slides to submit them to a modified Papanicolaou procedure (see e.g. page 10). The Papanicolaou stain can be carried out on a microscope slide (see e.g. page 26). The cells that were positive for the biomarkers can be counted to produce a percentage of positive cells (see e.g. page 23). The cancer type can be a carcinoma (see e.g. page 1-2). The patient can be treated with a single or multiple doses of an antibody (see e.g. page 18). The instant specification and claims references antibodies as immunotherapies (see e.g. instant specification paragraph [0148], for example), therefore the treatment of Fradet would meet the limitations of an immunotherapy. The patient can be a human (see e.g. Fradet abstract). The patients were suspected of having bladder cancer based on symptoms or history (see e.g. page 33). The assessment can include examining the cell membrane and vacuoles (see e.g. page 51). The method comprises a filtration see e.g. examples 8 and 9 on page 46-47).
It would have been obvious to one with ordinary skill in the art, at the time of the invention, to apply the principles of Fradet to the method of the reference patent as a known variation in the art. The Supreme Court set forth in KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), that if the scope and content of the prior art included a similar or analogous product, with differences between the claimed invention and prior art that were encompassed in known variation or in a principle known in the art, and one of ordinary skill in the art could have combined the elements as claimed by known methods, the claimed variation would have been predictable in to one of ordinary skill in the art. The method of the reference patent and Fradet are both staining methods that share many similarities and are variations within the same field of immunostaining and cytology. Thus, the combination of prior art references as combined provided a prima facie case of obviousness, absent convincing evidence to the contrary.
Neither Fradet the reference application teach treatment of a patient with a therapy such as pembrolizumab as recited in instant claim 68.
Necchi et al teach treatment of urothelial carcinoma with pembrolizumab before radical cystectomy (see e.g. abstract). Prior to treatment, patients were tested for PD-L1 expression by immunohistochemistry (see e.g. page 3354, right column). Responses were significantly enriched in patients with expression of PD-L1 (see e.g. page 3357, left column).
It would have been obvious to one with ordinary skill in the art, at the time of the invention, to apply the testing and treatment of Necchi to the method of the reference application in in view of Fradet. The reference application and Fradet describe methods for identifying biomarker expression, and optimized means for testing cells that are in suspension. Necchi identifies a specific combination of biomarker and treatment, wherein the biomarker predicts response to the treatment. The Supreme Court set forth in KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), that if the scope and content of the prior art included a similar or analogous product, with differences between the claimed invention and prior art that were encompassed in known variation or in a principle known in the art, and one of ordinary skill in the art could have combined the elements as claimed by known methods, the claimed variation would have been predictable in to one of ordinary skill in the art. Fradet, the reference application and Necchi all use antibodies to stain bladder cancer cells to measure specific biomarker expression. It would be a known variation in the art to select specific biomarkers that correspond to treatment response for application to a patient through biomarker expression assays. The detection of PD-L1 expression in the assay of the reference patent in view of Fradet would not require alterations in components or function of the method. In fact, one of skill in the art would be motivated to apply a known biomarker for treatment response to a method providing superior staining for detection of bladder cancer. Thus, the combination of prior art references as combined provided a prima facie case of obviousness, absent convincing evidence to the contrary.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 55-66, and 69-73 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of copending Application No. 17/928,039 (reference application) in view of Fradet et al (WO 98/12564; filed 9/5/97; published 3/26/98) and further in view of Oosterhuis et al (Cancer. 2000 Jun 1;88(11):2598-605).
Although the claims at issue are not identical, they are not patentably distinct from each other.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 1 is directed to a method of detecting bladder cancer in a patient, comprising: isolating urinary exfoliated cells from the patient; fixing the urinary exfoliated cells in an aqueous cell suspension; staining the urinary exfoliated cells with a liquid-based immunocytochemistry or chromogenic in-situ hybridization stain, or both; staining the urinary exfoliated cells with a diagnostic cytomorphologic stain; assessing the urinary exfoliated cells as comprising bladder cancer cells by the immunocytochemistry or chromogenic in-situ hybridization stain, or both, and the diagnostic cytomorphologic stain; thereby detecting bladder cancer in the patient.
Claim 55 is directed to the method of claim 1, wherein the urinary exfoliated cells are urinary sediment cells isolated from the urine sample by centrifugation.
Claim 56 is directed to the method of claim 1, wherein the immunocytochemistry or chromogenic in-situ hybridization stain, or both, is performed in an aqueous cell suspension.
Claim 57 is directed to the method of claim 56, wherein the immunocytochemistry or chromogenic in-situ hybridization stain, or both, comprises labeling one or more bladder cancer specific biomarkers.
Claim 58 is directed to the method of claim 57, wherein the one or more bladder cancer specific biomarkers are selected from the group consisting of S100P, p63, M344, LDQ10, 19A211, GATA-3, Ki-67, p16, Her-2, PD-L1, CTLA4, CK-17, CK-20, nmp-22, bladder tumor antigen (BTA), hTERT, and mini-chromosome maintenance protein 5 (MCM5).
Claim 59 is directed to the method of claim 1, wherein the diagnostic cytomorphologic stain is performed either: a) in an aqueous cell suspension; or b) after mounting the urinary exfoliated cells onto a solid substrate.
Claim 60 is directed to the method of claim 59, wherein the diagnostic cytomorphologic stain comprises Diff-Quik stain, Papanicolaou stain, Wright-Giemsa stain, hematoxylin/eosin stain, or a derivative or modification thereof.
Claim 61 is directed to the method of claim 59, wherein the solid substrate is a microscope slide.
Claim 62 is directed to the method of claim 1, wherein the assessing step includes counting the numbers of total bladder cancer cells, or percentage of biomarker positive cells among bladder cancer cells, or both.
Claim 63 is directed to the method of claim 62, wherein the bladder cancer cells comprise one or more bladder cancer specific biomarkers selected from the group consisting of S100P, p63, M344, LDQ10, 19A211, GATA-3, Ki-67, p16, Her-2, PD-L1, CTLA4, CK-17, CK- 20, nmp-22, bladder tumor antigen (BTA), hTERT, and mini-chromosome maintenance protein 5 (MCM5).
Claim 64 is directed to the method of claim 1, wherein the bladder cancer is urothelial carcinoma, squamous cell carcinoma, adenocarcinoma, small cell carcinoma, sarcoma, or any combination thereof.
Claim 65 is directed to the method of claim 1, further comprising treating the patient for bladder cancer.
Claim 66 is directed to the method of claim 65, wherein treating the patient for bladder cancer comprises surgery, chemotherapy, immunotherapy, targeted therapy, or radiation therapy, or any combination thereof.
Claim 67 is directed to the method of claim 66, wherein the chemotherapy comprises administration of cisplatin, carboplatin, fluorouracil, mitomycin, gemcitabine, methotrexate, vinblastine, doxorubicin, erdafitinib, afatinib, docetaxel, or paclitaxel, or any combination thereof.
Claim 68 is directed to the method of claim 66, wherein the immunotherapy comprises administration of Bacillus Calmette-Guerin (BCG), atezolizumab, avelumab, durvalumab, enfortumab, nivolumab, ipilimumab, trastuzumab, disitamab, PRS-343, or pembrolizumab, or any combination thereof.
Claim 69 is directed to the method of claim 65, wherein the patient is a human.
Claim 70 is directed to the method of claim 1, wherein the patient is selected to provide urinary exfoliated cells based on presentation of clinical symptoms of bladder cancer and/or being part of a population at high risk of developing bladder cancer.
Claim 71 is directed to the method of claim 1, wherein any one or more of the antibodies or binding fragments thereof set forth in Figure 3 are utilized.
Claim 72 is directed to the method of claim 1, wherein assessing the urinary exfoliated cells by the diagnostic cytomorphologic stain comprises assessing characteristics of the urinary exfoliated cells comprising nuclear features, shape or size of the nuclei or nucleoli; the density of chromatin; cytoplasmic elements such as mucins, fat droplets or neurosecretory granules; or cell membrane features such as membrane grooves, projections, or vacuoles.
Claim 73 is directed to the method of claim 1, wherein staining the urinary exfoliated cells with the liquid-based immunocytochemistry or chromogenic in-situ hybridization stain, and/or staining the urinary exfoliated cells with the diagnostic cytomorphologic stain comprises centrifugation or use of one or more inserts or transwells, wherein the one or more inserts or transwells comprise a porous membrane that permits aqueous solution to pass but retains the urinary exfoliated cells, such as a porous membrane having a pore size of 1, 2, 3, 4, 5, 6, 7, or 8pm or having a pore size within a range defined by any two of the aforementioned pore sizes and, optionally, wherein the one or more inserts or transwells further comprise a flange, protrusion, tab, or handle.
The reference application is directed to a multiple staining method for making immunohistochemical staining and/or nucleic acid chromogenic in situ hybridization staining and cell morphological staining that can be used for pathological diagnosis in a cell sample comprising preparing a cell suspension of the cell sample in a container, performing immunohistochemical staining and/or nucleic acid chromogenic in situ hybridization staining on cells in a cell suspension comprising adding antibodies that bind to an antigen, removing unbound antibody, adding a secondary antibody conjugated with a probe, removing the unbound secondary antibody, adding a chromogenic substrate, removing the excess chromogenic substrate, performing morphogenic staining for pathological diagnosis, smearing the stains on a slide (see e.g. claim 1). The method can also include washing the cells, centrifuging the cells, and discarding the supernatant (see e.g. claim 2). The cell morphological staining can be the same type of staining as the instant claims, such as Diff-Quik staining (see e.g. claim 3). The sample can be urine (see e.g. claim 5). The staining can probe cell membrane, cytoplasm, and/or cell nucleus (see e.g. claim 6).
The reference application does not teach detection of bladder cancer or labeling with specific bladder cancer markers.
Fradet teaches a non-invasive method for detecting bladder cancer comprising contacting shedded cells from the bladder, fixing said cells, reacting the cells with an immunological composition comprising mabs m344, 19A211, and LDQ10 for a sufficient time to obtain decorated cells, performing a combination of immunocytological and classical cytological analyses on decorated cells, and assessing the absence or presence of bladder cancer (see e.g. Fradet claim 1). The detection of the antibodies can be through fluorophore tags (see e.g. page 55). The M344 antigen has been described for bladder cancer (see e.g. page 4). The samples can contain voided urine samples(see e.g. page 26), which can include a sample with shedded sediment cells from the bladder (see e.g. page 10). . The method comprises both immunological assay and routine cytology in the same cell preparation (see e.g. page 10), and the cells can be fixed then blotted on microscope slides to submit them to a modified Papanicolaou procedure (see e.g. page 10). The Papanicolaou stain can be carried out on a microscope slide (see e.g. page 26). The cells that were positive for the biomarkers can be counted to produce a percentage of positive cells (see e.g. page 23). The cancer type can be a carcinoma (see e.g. page 1-2). The patient can be treated with a single or multiple doses of an antibody (see e.g. page 18). The instant specification and claims references antibodies as immunotherapies (see e.g. instant specification paragraph [0148], for example), therefore the treatment of Fradet would meet the limitations of an immunotherapy. The patient can be a human (see e.g. Fradet abstract). The patients were suspected of having bladder cancer based on symptoms or history (see e.g. page 33). The assessment can include examining the cell membrane and vacuoles (see e.g. page 51). The method comprises a filtration see e.g. examples 8 and 9 on page 46-47).
It would have been obvious to one with ordinary skill in the art, at the time of the invention, to apply the principles of Fradet to the method of the reference application as a known variation in the art. The Supreme Court set forth in KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), that if the scope and content of the prior art included a similar or analogous product, with differences between the claimed invention and prior art that were encompassed in known variation or in a principle known in the art, and one of ordinary skill in the art could have combined the elements as claimed by known methods, the claimed variation would have been predictable in to one of ordinary skill in the art. The method of the reference patent and Fradet are both staining methods that share many similarities and are variations within the same field of immunostaining and cytology. Thus, the combination of prior art references as combined provided a prima facie case of obviousness, absent convincing evidence to the contrary.
Neither the reference application nor Fradet teach antibodies of Figure 3 as recited in instant claim 71.
Oosterhuis teaches an detection of transitional cell carcinoma of the bladder with MIB-1 using immunostaining (see e.g. abstract and page 2599, left column).
It would have been obvious to one with ordinary skill in the art, at the time of the invention, to apply the MIB-1 antibody to the method of the reference application in view of Fradet. The reference application and Fradet describe methods for identifying biomarker expression, and optimized means for testing cells that are in suspension. Oosterhuis identifies a specific biomarker for detecting bladder cancer. The Supreme Court set forth in KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), that if the scope and content of the prior art included a similar or analogous product, with differences between the claimed invention and prior art that were encompassed in known variation or in a principle known in the art, and one of ordinary skill in the art could have combined the elements as claimed by known methods, the claimed variation would have been predictable in to one of ordinary skill in the art. The reference application, Fradet, and Oosterhuis all use antibodies to stain bladder cancer cells to measure specific biomarker expression. It would be a known variation in the art to select specific biomarkers that correspond to detection of bladder cancer for application to a patient through biomarker expression assays. The detection of Ki-67 expression in the assay of the reference patent in view of Fradet would not require alterations in components or function of the method. In fact, one of skill in the art would be motivated to apply a known biomarker for detection of bladder cancer to a method providing superior staining for detection of bladder cancer. Thus, the combination of prior art references as combined provided a prima facie case of obviousness, absent convincing evidence to the contrary.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claim is allowed.
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/ANDREA K MCCOLLUM/Examiner, Art Unit 1674
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