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 .
Election/Restrictions
Applicant’s election without traverse of claims 1-15 and 18-24 in the reply filed on 30 December 2025 is acknowledged.
Claims 16-17 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 30 December 2025.
Information Disclosure Statement
The information disclosure statement (IDS) submitted 25 July 2023 is considered, initialed, and attached hereto.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Claim Status
Claims 1-24 are pending.
Claims 16-17 are withdrawn from consideration as being drawn to a non-elected invention.
Accordingly, claims 1-15 and 18-24 are under examination.
Specification
The use of the term Alexa Fluor, Wes, Corning, Pall, Hyclone, Cytiva, JEOL, NanoSight, Malvern Panalytical, ExoView, Thermo Fisher Scientific, Orbitrap Fusion Lumos, nanoViper, Bio-Rad, ProteinSimple, Novus Biologicals, Abcam, Proteintech, R&D Systems, Invitrogen, Dako, Agilent, Nikon, Superblock, Lumencor, GraphPad Prism, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claim 1 is objected to because of the following informalities: the word "same" in line 7 should read as "sample". Appropriate correction is required.
Claim Interpretation
Claim 1 recites “wherein the combination of biomarkers is selected from ACSL4, IGSF8, ITGA2, ITGA5, ITGB3, and MYOF and optionally STX4 and/or optionally FOLR1”. Because the word ‘combination’ implies combining 2 or more things, this phrase is interpreted as requiring that the combination of biomarkers comprises 2 or more of ACSL4, IGSF8, ITGA2, ITGA5, ITGB3, and MYOF. Because STX4 and FOLR1 are recited as biomarkers that are ‘optionally’ part of the combination of biomarkers and recited separate from the list of ACSL4, IGSF8, ITGA2, ITGA5, ITGB3, and MYOF, the selection of 2 or more biomarkers is interpreted as being specifically from the list of ACSL4, IGSF8, ITGA2, ITGA5, ITGB3, and MYOF, but could include all of those as well as STX4 and FOLR1.
Where claims 2, 6, 15, 18, 23, and 24 recite the list “ACSL4, IGSF8, ITGA2, ITGA5, ITGB3, and MYOF and optionally STX4 and/or optionally FOLR1”, the list is interpreted as requiring all 6 of ACSL4, IGSF8, ITGA2, ITGA5, ITGB3, and MYOF but not requiring STX4 or FOLR1 because STX4 and FOLR1 are recited as being optional.
Claim Rejections - 35 USC § 112(b) - Indefiniteness
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
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 1-15 and 18-24 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 the limitation "the presence of the biomarkers" in lines 5-6. There is insufficient antecedent basis for this limitation in the claim. For the purpose of examination, this is interpreted as “the presence of the combination of biomarkers”. Claims 2-15 are also rejected based on their dependency on claim 1.
Claim 1 recites the limitations "the sample" and "the same" (interpreted as reading as ‘sample’, see Claim Objections) in lines 6 and 7. There is insufficient antecedent basis for this limitation in the claim. For the purpose of examination, this is interpreted as “the biological sample”. Claims 2-15 are also rejected based on their dependency on claim 1.
Claim 2 recites the limitation "the ACSL4, IGSF8, ITGA2, ITGA5, ITGB3, and MYOF and optionally STX4 and/or optionally FORL1" in line 2. There is insufficient antecedent basis for this limitation in the claim, since claim 1 recites only a selected combination of these biomarkers and does not recite this list as a whole.
Claim 2 recites the limitation "the presence of ACSL4, IGSF8, ITGA2, ITGA5, ITGB3, and MYOF" in lines 4-5. There is insufficient antecedent basis for this limitation in the claim, since only the presence of a selected combination of these biomarkers is claims 1 or 2.
Claim 2 recites the limitation "the " in lines 6-7. There is insufficient antecedent basis for this limitation in the claim, since only the increased amount of all of a selected combination of these biomarkers is recited in claims 1 or 2.
The metes and bounds of claim 6 are indefinite. Claim 6 depends upon claim 1, thus inheriting the method of claim 1 of reporting a diagnosis of cancer in a subject comprising the recited obtaining, measuring, determining, preparing, and providing steps. Claim 6 introduces an additional step of detecting biomarkers in a female human subject (not necessarily the same subject as claim 1). It is unclear how the step and sub-steps introduced in claim 6 relate to the steps of claim 1. Is the female human subject the same subject as in claim 1 or a different subject? Is the measuring step of claim 1 accomplished by sub-steps b) and c) in claim 6 or are these separate? Is the report in sub-steps e) and f) of claim 6 the same report as the report in claim 1? If the answers to any of these uncertainties are that this is not the same subject, not the same measuring step, or not the same report, how does the new subject, measurement, or report introduced by claim 6 relate to reporting a diagnosis of cancer in the subject of claim 1? These questions make it unclear what the metes and bounds of claim 6 are, therefore claim 6 and claims 7-15 that depend on claim 6 are rejected as indefinite.
Claim 6 recites the limitation "the plurality of extracellular vesicle-associated proteins" in line 11. There is insufficient antecedent basis for this limitation in the claim. Claims 7-15 are also rejected based on their dependency on claim 6.
Claim 6 recites the limitation "the report" in line 1. There is insufficient antecedent basis for this limitation in the claim. Claims 7-15 are also rejected based on their dependency on claim 6.
Claim 6 recites the limitation "the subject" in line 1. There is insufficient antecedent basis for this limitation in the claim. Claims 7-15 are also rejected based on their dependency on claim 6.
Claim 14 recites the limitation “applying secondary antibodies conjugated to biotin to the binding agents and bound extracellular vesicle-associated protein biomarkers, which are used as fluorescent reporters”. It is unclear whether “which are used as fluorescent reporters” refers to the secondary antibodies, the binding agents, the bound extracellular vesicle-associated protein biomarkers, or some unspecified combination thereof. This prevents one of ordinary skill in the art from understanding the metes and bounds of the claim.
Claim 15 recites the limitation “the ACSL4, IGSF8, ITGA2, ITGA5, ITGB3, and MYOF and optionally STX4 and/or optionally FORL1” in lines 2-3. There is insufficient antecedent basis for this limitation in the claim.
Claim 15 recites the limitation “the increased amount ACSL4, IGSF8, ITGA2, ITGA5, ITGB3, and MYOF and optionally STX4 and/or optionally FORL1” in lines 4-5. There is insufficient antecedent basis for this limitation in the claim.
Claim 18 recites the limitation "the plurality of extracellular vesicle-associated proteins" in lines 9-10. There is insufficient antecedent basis for this limitation in the claim. Claims 19-24 are also rejected based on their dependency on claim 18.
Claim 18 recites the limitation "the extracellular vesicle-associated protein biomarkers" in line 13. There is insufficient antecedent basis for this limitation in the claim. Claims 19-24 are also rejected based on their dependency on claim 18.
Claim 19 recites the limitation "the patient" in line 1. There is insufficient antecedent basis for this limitation in the claim.
Claim 19 recites the limitation "the performance" in lines 1-2. There is insufficient antecedent basis for this limitation in the claim.
Claim 23 recites the limitations "the detection of binding" in line 3, “the binding agents” in line 3, and “the extracellular vesicle-associated proteins of ACSL4, IGSF8, ITGA2, ITGA5, ITGB3, and MYOF and optionally STX4 and/or optionally FOLR1” in lines 3-5. There is insufficient antecedent basis for these limitations in the claim because each of these has 2 possible instances that they may be referring to (e.g., the detection of binding may refer to the detection of binding that occurs in claim 18 step d) or in the repeated performance of step d) recited in claim 23 line 2). Claim 24 is also rejected based on its dependency on claim 23.
Claim 23 recites the limitation "the report" in line 6. There is insufficient antecedent basis for this limitation in the claim because it may refer to either the report of claim 18 or the second report of claim 23. Claim 24 is also rejected based on its dependency on claim 23.
Claim Rejections - 35 USC § 112(d) - Dependent Form
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 13, 21, 22, and 24 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claims 13 and 22 recite the methods of claim 6 and claim 18, respectively, further comprising selecting the female human subject by at least one of a list of characteristics. The recited phrase “is positive for BRCA1, BRCA2 mutation or other cancer susceptibility genes” is interpreted as including the situation where a female human subject is positive for the BRCA1 gene (e.g., possesses the gene). All female humans are positive for the BRCA1 gene, because “BRCA1 is essential for repair of DNA double-strand breaks by homologous recombination, and hence for survival. Complete loss of its function is lethal during early embryonic development” (Seo et al. “Mechanism for survival of homozygous nonsense mutations in the tumor suppressor gene BRCA1”, Proc Natl Acad Sci U S A 115(20) pages 5241-5246 (2018), Abstract). Because all possible female human subjects are positive for BRCA1, claim 13 does not further limit claim 6 on which claim 13 depends and claim 22 does not further limit claim 18 on which claim 22 depends. Claim 21 recites a single limitation, "the method of claim 20, comprising the subject undergoing the treatment of ovarian cancer", which fails to further limit claim 20 on which claim 21 depends because claim 20 inherits via its dependency on claim 18 the limitation "the subject undergoes the treatment of ovarian cancer". Claim 24 recites a single, contingent limitation "performing a subsequent treatment if the second report provides an indication of ovarian cancer [...]", which is not required for the method to performed, so the limitation is not given patentable weight (see MPEP §2111.04 II.) and therefore does not further limit the method of claim 23 on which claim 24 depends. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 112(a) - Scope of Enablement
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 1-15 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of diagnosing ovarian cancer in a female human subject based on measuring the amount of protein products of a combination of the biomarkers ACSL4, IGSF8, ITGA2, ITGA5, ITGB3, and MYOF in cultured media from cells or tissue explants from fallopian tubes or ovarian cancer tumors, in fallopian tube or ovarian cancer tumor tissue, or in plasma, does not reasonably provide enablement for this method wherein the cancer is of a type other than ovarian cancer, the subject is of a type other than a female human, the measurement is of mRNA of the biomarkers rather than of protein of the biomarkers, the presence of cancer cells is determined by the presence of the combination of biomarkers instead of the amount, or the biological sample is of a type other than one of: cultured media from cells or tissue explants from fallopian tubes or ovarian cancer tumors, fallopian tube or ovarian cancer tumor tissue, or plasma. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Scope of the Claims/Nature of the Invention
The claims are drawn to methods for cancer diagnosis of a subject. In view of the recitation of “cancer” and “presence of cancer cells”, the claims broadly encompass ANY type of cancer. The recitation of “ovarian cancer” in claim 2 does not limit claim 1’s recitation of “cancer” and “cancer cells”, but merely limits some options of content of the report, so the recitation of “diagnosis of cancer” and steps involving “cancer cells” still encompass ANY type of cancer in claim 2.
In view of the recitation of “subject”, the claims 1-15 encompass both male and female human subjects as well as non-human subjects. Though claims 6-15 recite a female human subject, this recitation does not clearly limit the subject of claim 1, so claims 6-15 encompass the same subjects as claims 1-5.
The claims recite a second step of measuring presence or amount of a combination of biomarkers in the biological sample and a third step of determining whether the presence or amount of the combination of biomarkers indicates the presence of cancer cells. In view of the recitation “presence or amount”, claims 1-5 encompass determining the presence of cancer cells based on a measured mRNA presence, a measured mRNA amount, a measured protein presence, or a measured protein amount of any combination of the claimed biomarkers. Claims 3 and 5 specifically require measuring mRNA of the biomarkers (claim 3 implicitly through recitation of RT-PCR or RT-qPCR) and claim 4 specifically requires using a binding agent to bind with a protein form of the biomarkers, but none of these claims exclude using the other methods of measuring the presence or amount (rather, they recite that “the measuring and determining steps include”, emphasis added), so they still encompass measuring mRNA and protein presence and amount.
In view of the recitation of “biological sample”, the claims broadly encompass ANY type of biological sample (i.e., cell culture, serum, blood, hair, skin, fresh lung tissue, preserved brain tissue, etc.).
The nature of the invention requires a correlation between the measured presence and amount of mRNA and protein of any combination of biomarkers ACSL4, IGSF8, ITGA2, ITGA5, ITGB3, and MYOF in ANY biological sample from ANY subject with ANY type of cancer.
Teachings in the Specification and Examples
Regarding the type of cancer and type of biological sample, the specification teaches by comparing Fig. 6A2 with Figs. 6A3-6A5 as well as in Fig. 6B that the expression of the biomarkers ACSL4, IGSF8, ITGA2, ITGA5, ITGB3, MYOF, and FOLR1 differs between ovarian cancers and non-ovarian cancers. In the Examples section, the specification teaches identifying ACSL4, IGSF8, ITGA2, ITGA5, ITGB3, MYOF, FOLR1, and STX4 as biomarkers by comparing biological samples of conditioned media from cell lines and fresh tissue explants of FT (non-cancer fallopian tube) and HGSOC (ovarian cancer) ([088]). These biomarkers were further confirmed by immunohistochemistry on biological samples of primary and metastatic tumors and serous tubal intraepithelial carcinoma (STIC, a precursor lesion to ovarian cancer) tissue in comparison to healthy FT tissue (Figs. 4A-B; [098]). The specification also teaches the ability for these ACSL4, IGSF8, ITGA2, ITGA5, ITGB3, MYOF, and FOLR1 biomarkers to differentiate plasma biological samples of ovarian cancer patients from healthy controls ([0101-0103]; Tables 1 and 2).
Regarding the type of subject, the specification teaches that while ovarian cancer tends to occur in post-menopausal women, it can occur in women at younger ages ([004]). The example in the specification is based on the comparison of ovarian cancer cells with fallopian tube cells. Since females have ovaries and fallopian tubes, whereas males generally do not, the specification only teaches the diagnosis of ovarian cancer in female human subjects.
Regarding the correlation between a cancer and a measured presence or amount of mRNA or protein of a combination of the claimed biomarkers, the Examples section of the specification teaches identification of a correlation between the presence of cancer cells and differences in the amount of protein of the claimed biomarkers ([088-0103]). However, the specification teaches that there is not a difference in the presence of protein of the claimed biomarkers, since it teaches that protein of the claimed biomarkers is present in samples from both cancer and healthy control (FT) cell lines and tissues (“Among the proteins analyzed using Wes, ACSL4, IGSF8, ITGA2, ITGA5, ITGB3, MYOF and STX4 were consistently detect in all the tested FT and HGSOC cell line EVs (Figure 3)” [096]; “All transmembrane proteins were expressed to varying degrees in healthy FT tissue, and in both primary and metastatic tumors” [098]). Therefore, the specification teaches one of ordinary skill in the art that the mere presence of a combination of the biomarkers ACSL4, IGSF8, ITGA2, ITGA5, ITGB3, and MYOF would not be sufficient to indicate the presence of cancer cells in a subject, but does teach that the amount of protein of any combination of these biomarkers could be used to determine the presence of ovarian cancer cells in a female human subject.
State of the Art and Unpredictability of the Art
While methods of measuring mRNA and protein expression are known in the art, methods of correlating expression levels with a phenotype such as cancer are highly unpredictable. The unpredictability will be discussed below.
The claims broadly encompass being able to diagnose any type of cancer based on the presence or amount of mRNA or protein of a combination of biomarkers selected from ACSL4, IGSF8, ITGA2, ITGA5, ITGB3, and MYOF. The prior art of Xu et al. (“A Comparative Analysis of Gene-Expression Data of Multiple Cancer Types”, PLoS One 5(10):e13696 (2010)) teaches that they sought to identify genes that could be used as indicators for cancer in general or for a group of cancers. They examined differentially expressed genes with at least 2-fold changes between cancer and corresponding control tissues across seven different cancer types (breast, colon, kidney, lung, pancreas, prostate, stomach). Only 85 genes were differentially expressed across 3 cancer types, 19 genes were differentially expressed across 4 cancer types, and 5 genes were differentially expressed among 5 cancer types (page 5). Thus, it is highly unpredictable as to whether the findings in the specification regarding the correlation of the amount of ACSL4, IGSF8, ITGA2, ITGA5, ITGB3, and MYOF protein in ovarian cancer compared control cell lines and tissues could be extrapolated to any type of cancer.
The claims broadly encompass the measurement of the presence and the amount of RNA levels and protein levels and the determination of the presence of cancer cells based on any of these measurements. Therefore, it is relevant to point out the unpredictability as to whether or not a measure of RNA expression is indicative of the level of protein expression in a sample. Chan (“Integrating Transcriptomics and Proteomics”, G & P magazine: Vol. 6, No. 3, pages 20-26, (2006)) teaches that cells have elaborate regulatory mechanisms at the level of transcription, post-transcription, and post-translation (page 1, paragraph 5) and that transcript and protein abundance measurements may only have a weak correlation (page 1, paragraph 6) and may not be concordant (page 2, paragraph 11). Thus, it is unpredictable as to whether or not the results of the example in the specification demonstrating the correlation of a measurement of the amount of protein with the presence of cancer cells would be applicable to methods encompassing the correlation of a measurement of the amount or presence of RNA with the presence of cancer cells.
The claims broadly encompass diagnosing cancer in a human subject that may be of any sex as well as in a non-human subject. However, the data presented in the specification is based on the comparison of ovarian cancer cells with fallopian tube cells. Since females have ovaries and fallopian tubes, whereas males generally do not, the specification only teaches the diagnosis in female human subjects. The prior art teaches that there is a large amount of unpredictability with regard to comparing results from gene expression analysis in humans to even closely related animals. For example, Coleman (“Of mouse and man – what is the value of the mouse in predicting gene expression in humans?” Drug Discov Today, 8(6) pages 233-235 (2003)) found that while gene expression patterns between mice and humans shared some degree of similarity, the basic patterns of gene expression differed and that there was no general rule for predicting gene expression (page 2, paragraph 3 through page 3). Coleman concluded that “The validity of mouse or other animal species as a human surrogate should not be assumed.” These teachings of Coleman support the finding that there is no predictable means for determining whether the presence or amount of mRNA or protein that is predicative of cancer in a human subject will also be predictive of cancer in a representative number of non-human subjects. The specification only provides support for female human subjects.
The claims broadly encompass diagnosing cancer based on the presence or amount of mRNA or protein of a combination of biomarkers in any type of biological sample. However, the specification only provides analysis of the amount of protein of the biomarkers in samples of cultured media from FT and HGSOC cell lines and tissue explants, of tumor and FT tissues, and of plasma of HGSOC patients and healthy subjects. Therefore, it is highly unpredictable if the amount of protein of biomarkers observed in, for example, cultured media from HGSOC tissue explants could be extrapolated to other sample types encompassed by the claim (e.g., hair, preserved brain tissue, etc.). The prior art of Whitehead et al. (“Variation in tissue-specific gene expression among natural populations”, Genome Biol volume 6, article R13 (2005)) teaches that variation in gene expression is extensive among tissues (abstract). Whitehead et al. further teaches that many different cancers have unique tissue specific patterns of gene expression (page 1, paragraph 1). The specification teaches that different amounts of protein of the biomarkers is observed in cultured media from FT and HGSOC cell lines and tissue explants, in tumor and FT tissues, and in plasma from HGSOC patients and healthy subjects. There is no analysis in the specification of the amount of the protein of the biomarkers in other sample types (hair, preserved brain tissue, etc.) obtained from subjects with ovarian cancer. Thus, in the absence of evidence to the contrary it is highly unpredictable if the amount of the protein of the biomarkers in other sample types is useful in determining the presence of ovarian cancer cells in the subject, much less cancer cells of any type of cancer. The specification only provides support for the determination of the presence of ovarian cancer cells from biological samples of cultured media from FT and HGSOC cell lines and tissue explants, of tumor and FT tissues, and of plasma from HGSOC patients and healthy subjects.
Quantity of Experimentation
The quantity of experimentation necessary to enable the full scope of the claims is undue and one of ordinary skill in the art would have little if any reasonable expectation of success in achieving enablement of the full scope of the claims. In support of this position, it is noted that the claimed methods encompass being able to diagnose ANY type of cancer based on the presence or amount of mRNA or protein of any combination of biomarkers selected from ACSL4, IGSF8, ITGA2, ITGA5, ITGB3, and MYOF in ANY type of biological sample from ANY human or non-human subject.
In order to practice the breadth of the claimed invention one of ordinary skill in the art would first have to gather samples from human and non-human subjects having a sufficient number of different cancer types to be representative of every type of cancer in every type of subject. The samples would need to include tumor tissue, control tissue, and a sufficient number of different sample types to be representative of every type of biological sample. Then the mRNA and protein level of ACSL4, IGSF8, ITGA2, ITGA5, ITGB3, and MYOF would have to be measured. Then sophisticated data analysis would have to be conducted to determine which combinations of two or more of ACSL4, IGSF8, ITGA2, ITGA5, ITGB3, and MYOF could be used to diagnose all of the different cancer types, and would have to find that the presence or amount of all possible combinations could diagnose all cancer types in all sample types of all subject types. The specification has not done any of the above. The results of such experimentation are highly unpredictable.
The amount of experimentation that would be required to practice the full scope of the claimed invention and the amount of time and cost this experimentation would take supports the position that such experimentation is undue (see MPEP §2164.06).
Conclusions
Herein, although the level of ordinary skill in the art is high, given the lack of disclosure in the specification and in the prior art and the unpredictability of the art, it would require undue experimentation for one of ordinary skill in the art to make and use the full scope of the invention as broadly claimed in claims 1-15.
Claims 18-24 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of treating a female human subject that has ovarian cancer for ovarian cancer involving detecting binding of the extracellular vesicle-associated proteins ACSL4, IGSF8, ITGA2, ITGA5, ITGB3, and MYOF in cultured media from cells or tissue explants from fallopian tubes or ovarian cancer tumors, in fallopian tube or ovarian cancer tumor tissue, or in plasma, does not reasonably provide enablement for this method wherein the subject does not have ovarian cancer or the biological sample is of a type other than one of: cultured media from cells or tissue explants from fallopian tubes or ovarian cancer tumors, fallopian tube or ovarian cancer tumor tissue, or plasma. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Scope of the Claims/Nature of the Invention
The claims are drawn to methods for ovarian cancer treatment of a female human subject. In view of the recitation of “a female human subject” with no requirement that the female human subject have ovarian cancer and the recitation “providing the subject to get treatment for the ovarian cancer, wherein the subject undergoes treatment for ovarian cancer” claims 18-24 encompass every female human subject undergoing treatment for ovarian cancer regardless of whether they have ovarian cancer or not.
In view of the recitation of “biological sample”, the claims broadly encompass ANY type of biological sample (i.e., cell culture, serum, blood, hair, skin, fresh lung tissue, preserved brain tissue, etc.).
The nature of the invention requires a method of treating any female human subject (that may or may not have ovarian cancer) for ovarian cancer involving the detection of binding of the extracellular vesicle-associated proteins ACSL4, IGSF8, ITGA2, ITGA5, ITGB3, and MYOF from ANY biological sample from the female human subject.
Teachings in the Specification and Examples
Regarding the type of biological sample, in the Examples section, the specification teaches identifying ACSL4, IGSF8, ITGA2, ITGA5, ITGB3, MYOF, FOLR1, and STX4 extracellular vesicle-associated proteins as biomarkers by comparing biological samples of conditioned media from cell lines and fresh tissue explants of FT (non-cancer fallopian tube) and HGSOC (ovarian cancer) ([088]). These biomarkers were further confirmed by immunohistochemistry on biological samples of primary and metastatic tumors and serous tubal intraepithelial carcinoma (STIC, a precursor lesion to ovarian cancer) tissue in comparison to healthy FT tissue (Figs. 4A-B; [098]). The specification also teaches the ability for the ACSL4, IGSF8, ITGA2, ITGA5, ITGB3, MYOF, and FOLR1 extracellular vesicle-associated proteins to differentiate plasma biological samples of ovarian cancer patients from healthy controls ([0101-0103]; Tables 1 and 2).
Regarding the claimed treatment for ovarian cancer of both female human subjects with ovarian cancer and without ovarian cancer, the specification teaches specifically treating cancer after an identification that a female human subject has ovarian cancer (“a method for treating a female human for ovarian cancer is provided [….] preparing a report that the female human has cancer, and then treating the cancer” emphasis added [084]). The ordering in this phrasing of the specification limits the disclosed cancer treatment (such as “chemotherapy, radiation therapy, surgical removal of the fallopian tubes […] or the ovarian cancer” [085]) to being provided to a female human subject that has ovarian cancer.
State of the Art and Unpredictability of the Art
The claims broadly encompass methods of treating cancer involving detection of binding of the extracellular vesicle-associated proteins ACSL4, IGSF8, ITGA2, ITGA5, ITGB3, and MYOF using any type of biological sample from a female human subject. However, the specification only provides analysis of the amount of the extracellular vesicle-associated proteins in samples of cultured media from FT and HGSOC cell lines and tissue explants, of tumor and FT tissues, and of plasma of HGSOC patients and healthy subjects. Therefore, it is highly unpredictable if the binding of the extracellular vesicle-associated proteins observed in, for example, cultured media from HGSOC tissue explants could be extrapolated to other sample types of samples encompassed by the claim (e.g., hair, preserved brain tissue, etc.). The prior art of Whitehead et al. (“Variation in tissue-specific gene expression among natural populations”, Genome Biol volume 6, article R13 (2005)) teaches that variation in gene expression is extensive among tissues (abstract). Whitehead et al. further teaches that many different cancers have unique tissue specific patterns of gene expression (page 1, paragraph 1). Furthermore, the prior art of Kang et al. (“Biodistribution of extracellular vesicles following administration into animals: A systematic review” J Extracell Vesicles 10(8):e12085 (2021)) teaches that while the biodistribution of extracellular vesicles is largely to the liver, lungs, kidney, and spleen (abstract), individual studies have shown that EVs from different cell sources possess different biodistribution patterns (page 18, paragraph 2), demonstrating the unpredictability of whether the extracellular vesicle-associated proteins that are detected in the disclosed samples of the specification would also be detected in other samples (e.g., hair, preserved brain tissue, etc.). The specification teaches that different amounts of the extracellular vesicle-associated proteins are observed in cultured media from FT and HGSOC cell lines and tissue explants, in tumor and FT tissues, and in plasma from HGSOC patients and healthy subjects. There is no analysis in the specification of the amount of the extracellular vesicle-associated proteins in other samples types (e.g., hair, preserved brain tissue, etc.) obtained from subjects with ovarian cancer. Thus, in the absence of evidence to the contrary it is highly unpredictable if the amount of the extracellular vesicle-associated proteins in other sample types is useful in treating ovarian cancer in a female human subject. The specification only provides support for the treatment of ovarian cancer involving detection of the extracellular vesicle-associated proteins in biological samples of FT and HGSOC cell lines and tissue explants, of tumor and FT tissues, and of plasma from HGSOC patients and healthy subjects.
One of ordinary skill in the art of treating ovarian cancer is a medical professional that recommends “treatments for which the potential benefits outweigh the risks of harm” (Shmerling, “First, do no harm”, Harvard Health Publishing, https://www.health.harvard.edu/blog/first-do-no-harm-201510138421, 2020; page 3, paragraph 2). Cancer treatments such as the chemotherapy disclosed in the specification ([085]) and specified in claim 20 possess significant risks to patients. Smith (“What Happens to Your Body During Chemo? 5 Common Side Effects” Healthline, https://www.healthline.com/health/cancer/how-chemo-affects-the-body, 2019, version retrieved from WayBack Machine snapshot dated 22 July 2019) teaches that chemotherapy can harm a patient by causing anemia, neutropenia, blood clotting issues, hair loss, and digestive tract side effects (entire reference). One of ordinary skill in the art would therefore seek to avoid administering chemotherapy and its associated risks and harms to a patient that would not benefit from the chemotherapy, such as a patient that does not have cancer. The art thus does not enable one of ordinary skill in the art to provide treatment for ovarian cancer to a female human subject that does not have ovarian cancer.
Quantity of Experimentation
The quantity of experimentation necessary to enable the full scope of the claims is undue and would have little if any reasonable expectation of success in achieving enablement of the full scope of the claims. In support of this position, it is noted that the claimed methods encompass treating ovarian cancer involving detection of the extracellular vesicle-associated proteins ACSL4, IGSF8, ITGA2, ITGA5, ITGB3, and MYOF in ANY type of biological sample from a female human subject and having the female human subject undergo treatment for ovarian cancer regardless of whether the female human subject has ovarian cancer or not.
In order to practice the breadth of the claimed invention one of ordinary skill in the art would first have to gather samples from female human subjects having ovarian cancer and control subjects. The samples would need to include tumor tissue, control tissue, and a sufficient number of different sample types to be representative of every type of biological sample. Then the binding of extracellular vesicle-associated proteins ACSL4, IGSF8, ITGA2, ITGA5, ITGB3, and MYOF would have to be measured from all of these samples. Then sophisticated data analysis would have to be conducted to determine how the detection of binding of these extracellular vesicle-associated proteins in every sample type can be used in the treatment of ovarian cancer. Furthermore, separate experiments would need to be undertaken to develop treatments for ovarian cancer that have such a little risk for harm that they may be ethically applied to all female human subjects regardless of whether they have ovarian cancer or not (to enable claim 20 this treatment would also have to be a type of chemotherapy, radiation therapy, surgical removal of ovarian cancer, or combination thereof). The specification has not done any of the above. The results of such experimentation are highly unpredictable.
The amount of experimentation that would be required to practice the full scope of the claimed invention and the amount of time and cost this experimentation would take supports the position that such experimentation is undue (see MPEP §2164.06).
Conclusions
Herein, although the level of ordinary skill in the art is high, given the lack of disclosure in the specification and in the prior art and the unpredictability of the art, it would require undue experimentation for one of ordinary skill in the art to make and use the full scope of the invention as broadly claimed in claims 18-24.
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 1-15 and 18-24 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural phenomenon ands without significantly more. While the claims are directed to processes (methods), and therefore meet step 1 of the subject matter eligibility test (see MPEP §2106.03), the claims recite the natural correlation between ACSL4, IGSF8, ITGA2, ITGA5, ITGB3, and MYOF and optionally STX4 and/or optionally FOLR1 and cancer, as well as the mental processes of determining the presence of cancer cells based on measurements (claims 1-15 only) and preparing a report. The natural correlation is a natural phenomenon because it describes a consequence of the human body (e.g., a change in ACSL4 protein amount due to disease). The mental process of determining the presence of cancer cells based on measurements is an abstract idea because it can reasonably be performed in the human mind (e.g., visually looking at one measurement compared to another on a computer screen and determining they are different values). The mental process of preparing a report is an abstract idea because it can be performed in the human mind by hand (e.g., written down with pen and paper).
Step 2A of the subject matter eligibility test requires a two-pronged analysis. Prong One asks: does the claim recite an abstract idea, law of nature, or natural phenomenon? As discussed in MPEP §2106.04 II. A. 1., the meaning of “recites” is “set forth” or “describes”. That is, a claim recites a judicial exception when the judicial exception is “set forth” or “described” in the claim. In the instant case, the claims describe a natural phenomenon (the natural correlation between ACSL4, IGSF8, ITGA2, ITGA5, ITGB3, and MYOF and optionally STX4 and/or optionally FOLR1 and cancer), a first abstract idea (the mental process of determining the presence of cancer cells based on measurements), a second abstract idea (the mental process of preparing a report) and, in claim 23, a third abstract idea (the mental process of preparing a second report).
Prong Two of the analysis under step 2A asks: does the claim recite additional elements that integrate the judicial exception into a practical application of the judicial exception? As discussed in MPEP §2106.04 II. A. 2., “Because a judicial exception is not eligible subject matter, Bilski, 561 U.S. at 601, 95 USPQ2d at 1005-06 (quoting Chakrabarty, 447 U.S. at 309, 206 USPQ at 197 (1980)), if there are no additional claim elements besides the judicial exception, or if the additional claim elements merely recite another judicial exception, that is insufficient to integrate the judicial exception into a practical application. See, e.g., RecogniCorp, LLC v. Nintendo Co., 855 F.3d 1322, 1327, 122 USPQ2d 1377 (Fed. Cir. 2017) (“Adding one abstract idea (math) to another abstract idea (encoding and decoding) does not render the claim non-abstract”); Genetic Techs. V. Merial LLC, 818 F.3d 1369, 1376, 118 USPQ2d 1541, 1546 (Fed. Cir. 2016) (eligibility “cannot be furnished by the unpatentable law of nature (or natural phenomenon or abstract idea) itself.”). For a claim reciting a judicial exception to be eligible, the additional elements (if any) in the claim must “transform the nature of the claim” into a patent-eligible application of the judicial exception, Alice Corp., 573 U.S. at 217, 110 USPQ2d at 1981, either at Prong 2 or in Step 2B.” The considerations to be used are set forth at MPEP §2106.05(a) through (c) and (e) through (h). Turning to those sections of the MPEP:
MPEP §2106.05(a) has to do with improvements to the functioning of a computer or to any other technology or technical field. The claims at issue do not improve the functioning of a computer or other technology. While the instant claims recite steps of obtaining a biological sample from the subject; measuring the presence or amount of a combination of biomarkers in the biological sample wherein the combination of biomarkers is selected from ACSL4, IGSF8, ITGA2, ITGA5, ITGB3, and MYOF and optionally STX4 and/or optionally FOLR1; determining whether the presence or amount of the combination of biomarkers indicates the presence of cancer cells in the subject, wherein the measuring and determining steps include RT-PCR, RT-qPCR, using a binding agent to bind with the protein form of each of the biomarkers and detecting binding of the binding agent, or using a nucleic acid binding agent to hybridize with a mRNA form of each of the biomarkers and detecting hybridization of the nucleic acid binding agent; preparing a report on the presence of cancer cells in the subject, wherein the report includes an association of the combination of biomarkers and the presence of cancer cells and one or more of the identification, measurement data, statements, and listing recited in claim 2; obtaining extracellular vesicle-associated proteins from a biological sample from a female human subject selected by at least one of being suspected of having ovarian cancer, being positive for BRCA1, BRCA2 mutation, or other cancer susceptibility genes, being in a risk group for developing ovarian cancer, or being devoid of symptoms of ovarian cancer; providing a panel of binding agents wherein the binding agents are configured to bind with extracellular vesicle-associated proteins ACSL4, IGSF8, ITGA2, ITGA5, ITGB3, and MYOF and optionally STX4 and/or optionally FOLR1, the binding agents are selected from antibodies, antibody fragments, aptamers, or combinations thereof, and the panel of binding agents are selective for at least ACSL4, IGSF8, ITGA2, ITGA5, ITGB3, MYOF, FOLR1, and STX4; assaying for and detecting binding of binding agents of the panel with the extracellular vesicle-associated proteins wherein the assaying is a protein binding assay where each binding agent binds with a respective extracellular vesicle-associated protein biomarker and further comprises applying secondary antibodies conjugated to biotin to the binding agents and bound extracellular vesicle-associated protein biomarkers which are used as fluorescent reporters and quantifying levels of the extracellular vesicle-associated protein biomarkers using fluorescence wherein the levels are higher than control proteins; preparing a report on the detection of binding, wherein the report includes an association of the combination of biomarkers and the presence of cancer cells and one or more of the identification, measurement data, statements, and listing recited in claim 15, providing a report to the subject or to a medical entity or medical practitioner, providing the subject to get a treatment for ovarian cancer wherein the subject undergoes the treatment and the treatment is selected from chemotherapy, radiation therapy, surgical removal of the ovarian cancer, or a combination thereof; monitoring the patient during the performance of the treatment for ovarian cancer; performing the obtaining through detecting steps again after the subject undergoes treatment, preparing a second report, and providing the second report; and performing a subsequent treatment if the second report provides an indication of ovarian cancer the claims do not improve upon any methods claimed. The claims merely use existing methods for these steps. Note that MPEP §2106.05(a) indicates that “[u]sing well-known standard laboratory techniques to detect enzyme levels in a bodily sample” is an example that the courts have indicated may not be sufficient to show an improvement to technology. That the above steps were well known in the prior art will be shown below.
MPEP §2106.05(b) has to do with whether the claims involve the use of a particular machine. In this case, the claims do not involve the use of a particular machine. Even if some conventional machine were recited in the claims, like a specific kind of PCR machine, further considerations such as the particularity or generality of the recited machine must be taken into account, as well as whether the involvement of the machine is merely extra-solution activity. MPEP §2106.05(g) describes “extra-solution activity”, noting that “[d]etermining the level of a biomarker in blood” is an example of “mere data gathering” which the courts have found to be insignificant extra-solution activity.
MPEP §2106.05(c) has to do with whether the claims involve a particular transformation. Here, none of the limitations of the claims involve a particular transformation. For example, measuring presence or amount of a protein biomarker does not transform that protein biomarker into something else.
MPEP §2106.05(e) has to do with “other meaningful limitations”. The additional limitations in the instant case are those described in the above discussion of MPEP §2106.05(a) excluding the steps of determining whether the presence or amount of the combination of biomarkers indicates the presence of cancer cells in the subject, preparing a report on the presence of cancer cells in the subject, and preparing a report on the detection of binding. These limitations are not considered “meaningful limitations”. MPEP §2106.05(e) states: “The phrase “meaningful limitations” has been used by the courts even before Alice and Mayo in various contexts to describe additional elements that provide an inventive concept to the claim as a whole.” However, as will be discussed below, these limitations do not arrive at an inventive concept. As has been discussed, they represent insignificant extra-solution activity, i.e. “data gathering”. In addition, to identify whether the treatment steps represent meaningful limitations, MPEP §2106.04(d)(2) must be considered, which states that “[a] claim reciting a judicial exception is not directed to the judicial exception if it also recites additional element(s) demonstrating that the claim as a whole integrates the exception into a practical application. One way to demonstrate such integration is when the additional elements apply or use the recited judicial exception to effect a particular treatment or prophylaxis for a disease or medical condition” and that “[t]he treatment or prophylaxis limitation must be "particular," i.e., specifically identified so that it does not encompass all applications of the judicial exception(s).” Because the relevant instant claims either provide for only a general treatment for ovarian cancer (claims 18-19, 21-24) or for a treatment from the list of “chemotherapy, radiation therapy, surgical removal of the ovarian cancer, or combinations thereof” (claim 20) which is not specifically identified sufficiently such that it does not encompass all general treatments of ovarian cancer, these do not represent particular treatments or meaningful limitations under MPEP §2106.04(d)(2) and §2106.05(e), respectively.
MPEP §2106.05(f) raises the question as to whether the additional elements recited in the claim represent “mere instructions to apply an exception”. The additional elements recited in the claims (see additional limitations in the discussion of MPEP §2106.05(e)) amount to mere instructions to apply the natural correlation and mental processes, since the obtaining of particular samples from particular subjects and measuring the presence or amount or binding with known analysis techniques serve as mere conventional steps taken for the purpose of gathering data which any practical use of the natural correlation would require, and providing a report to the subject or to a medical entity or medical practitioner is a mere conventional step taken for the purpose of having the relevant parties receive the information on the report which any practical use of the mental process of preparing a report would require.
MPEP 2106.05(g) has to do with whether the additional elements of the claim amount to insignificant extra-solution activity. MPEP 2106.05(g) notes that “[d]etermining the level of a biomarker in blood” is an example of “mere data gathering” which the courts have found to be insignificant extra-solution activity. Likewise, MPEP §2106.05(g) notes that “[p]erforming clinical tests on individuals to obtain input for an equation” also represents insignificant extra-solution activity. This closely aligns with the additional limitations of obtaining, measuring, providing a panel of binding agents, assaying, and detecting in the instant claims.
MPEP §2106.05(h) has to do with whether the additional elements amount to more than generally linking the use of a judicial exception to a particular technological environment or field of use. Here, the recitations of the methods being used to report a diagnosis of cancer (claims 1-15) or treat ovarian cancer (claims 18-24) are considered “field of use”. However, as MPEP §2106.05(h) indicates, such limiting to a particular “field of use” does not confer patentability on otherwise ineligible subject matter.
In addition to the considerations under MPEP §2106.05(a) through (c) and (e) through (h) analyzed under step 2A prong 2, in step 2B these considerations and MPEP §2106.05(d) are used to determine whether the claims include additional elements that are sufficient to amount to significantly more than the judicial exception (i.e. whether they provide an inventive concept) (see MPEP §2106 III.). MPEP §2106.05(d) notes that courts have recognized that “[d]etermining the level of a biomarker in blood by any means” is “well-understood, routine, conventional activity” or “insignificant extra-solution activity”. This closely aligns with the additional limitations of obtaining, measuring, providing a panel of binding agents, assaying, and detecting in the instant claims. Additionally, the limitation of providing a report to the subject or to a medical entity or medical practitioner is merely an additional element that is well-understood, routine, conventional activity because reports containing results of medical assays are routinely presented to subjects, medical entities, and medical practitioners, as seen in art such as Lu et al. (in IDS filed 25 July 2023)(“A two stage ovarian cancer screening strategy using the risk of ovarian cancer algorithm (ROCA) identifies early stage incident cancers and demonstrates high positive predictive value” Cancer 119(19) pages 3454-3461 (2013)): “the ROCA score was communicated to the participant’s recruitment site. Investigators at each study site communicated the risk scores and screening recommendations to the patients” (page 4 paragraph 3). Additionally, the treatment steps fail to amount to significantly more than the judicial exception due to their generality failing to create any meaningful limitation, as discussed with regard to MPEP §2106.04(d)(2) above.
Having considered the factors discussed in MPEP §2106.05(a)-(h), as well as the prior art exemplified by Lu et al., it is clear that the additional elements recited in the claims, whether considered individually or as a combination, neither integrate the judicial exceptions into a practical application in such a way as to provide meaningful limits on the use of the judicial exceptions nor recite additional elements that amount to significantly more than the judicial exceptions. Therefore, claims 1-15 and 18-24 are here rejected under 35 U.S.C. 101.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-3 are rejected under 35 U.S.C. 103 as being unpatentable over Graeber et al. (US 2022/0244263, effectively filed date 28 May 2019), herein Graeber, in view of Lu et al. (in IDS filed 25 July 2023)(“A two stage ovarian cancer screening strategy using the risk of ovarian cancer algorithm (ROCA) identifies early stage incident cancers and demonstrates high positive predictive value” Cancer 119(19) pages 3454-3461 (2013)), herein Lu.
Regarding claim 1, Graeber teaches a method of getting a diagnosis of cancer in a subject (“a method […] for diagnosing a SCN or SRBCT cancer” [0012]), comprising: obtaining a biological sample from the subject (“methods involve obtaining a biological sample from a subject” [0124]); measuring presence or amount of a combination of biomarkers in the biological sample, wherein the combination of biomarkers is selected from ACSL4, IGSF8, ITGA2, ITGA5, ITGB3, and MYOF and optionally STX4 and/or optionally FOLR1 (“measuring the expression level of one or more biomarkers from Tables 1-3 in a biological sample from the patient [0012]; “ACSL4” Table 1, page 133, right column; “IGSF8” Table 1, page 110, right column; “ITGA2” Table 1, page 137, right column; “ITGA5” Table 1, page 139, right column; “ITGB3” Table 1, page 120, right column; “MYOF” Table 1, page 146, left column; “STX4” Table 1, page 117, left column; “FOLR1” Table 1, page 150, right column), wherein the presence of the biomarkers in the sample indicates presence of cancer cells in the subject, wherein an increased amount of the biomarkers in the sample indicates presence of cancer cells in the subject; determining whether the presence or amount of the combination of biomarkers indicates the presence of cancer cells in the subject (“comparing the expression level of the at least one biomarker to a control level of expression, wherein the control level of expression comprises the level of expression of the biomarkers in a SCN or SRBCT cancer; and diagnosing the patient as having a SCN or SRBCT cancer when the level of expression of the measured biomarker is not substantially different from the control level of expression” [0012]); and preparing a report on the presence of cancer cells in the subject (“the method further comprises calculating a risk score for the patient” [0026]), wherein the report includes an association of the combination of biomarkers and the presence of cancer cells (“in some embodiments, the risk score indicates the risk for having SCN or SBRCT cancer” [0026]).
Regarding claim 1, however, Graeber does not teach providing the report to the subject or to a medical entity or medical practitioner. This deficiency is made up for in the teachings of Lu.
Regarding claim 1, Lu teaches preparing reports concerning a patient’s cancer risk and providing those reports to subjects/patients, medical entities, and medical practitioners (“CA125 II assays were performed at MD Anderson Cancer Center using the Roche platform. Values were transmitted to the data coordinating center at Massachusetts General Hospital where the ROCA was applied and the patient’s risk was calculated” page 4, paragraph 2, the values transmitted are a report that is provided (transmitted) to a medical entity (Massachusetts General Hospital); “the ROCA score was communicated each time to the participant’s recruitment site. Investigators at each study site communicated the risk scores and screening recommendations to the patients” page 4, paragraph 3, the ROCA scores are a report of a cancer risk and are being provided from Massachusetts General Hospital to the subject (patients), a medical entity (recruitment site), and a medical practitioner (investigator)). Lu also teaches that it is advantageous to provide the report to the subject and medical practitioners, since depending on the contents of the report (what the ROCA risk is) different recommendations for ovarian cancer screening would be recommended to the patient (“if a patient’s ROCA risk of ovarian cancer is less than 1 in 2000 (called “normal risk”), the recommendation is for the woman to return for a repeat CA125 in one year […] (“intermediate risk”), the recommendation is to return for a repeat CA125 in three months […] (“elevated risk”), the recommendation is for a transvaginal ultrasound and referral to a gynecologic oncologist” page 3, paragraph 4 – page 4, paragraph 1).
Regarding claim 2, Lu teaches that the report may include a listing of medical entities that perform, oversee, or control the treatments for ovarian cancer (“referral to a gynecologic oncologist” page 4, paragraph 1).
Regarding claim 3, Graeber teaches that the measuring and determining steps include reverse-transcription polymerase chain reaction or reverse-transcription quantitative polymerase chain reaction to determine the presence or amount of the combination of biomarkers (“aspects of the methods include assaying nucleic acids to determine expression levels” [0140]; “a number of difference[sic] assays could be employed to analyze nucleic acids […] such assays include […] quantitative PCR, RT-PCR” [0142]).
In view of Lu’s teaching of an advantage to providing reports on cancer risk to subjects, medical entities, and medical practitioners, it would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to combine the teachings of Graeber with the teachings of Lu to obtain the claimed invention. Because Graeber’s method of diagnosis generates a report on the risk of subject having cancer, one of ordinary skill in the art would be motivated to combine the method with Lu’s teaching of providing reports on cancer risk to subjects/patients, medical entities, and medical practitioners in order for an appropriate recommendation of later screening, treating, or other actions to be taken. One of ordinary skill in the art would have a reasonable expectation of success because providing the report to a subject, medical entity, or medical practitioner has no impact on the method of diagnosis that generates the report and both the methods of Graeber and Lu produce reports related to a subject’s cancer risk. Therefore, the invention as a whole of claims 1-3 would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention.
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Graeber et al. (US 2022/0244263, effectively filed date 28 May 2019), herein Graeber, in view of Lu et al. (in IDS filed 25 July 2023)(“A two stage ovarian cancer screening strategy using the risk of ovarian cancer algorithm (ROCA) identifies early stage incident cancers and demonstrates high positive predictive value” Cancer 119(19) pages 3454-3461 (2013)), herein Lu, as applied to claims 1-3 above, and as evidenced by He et al. (“Chapter Three - Northern Blotting” Methods Enzymol 530, pages 75-87 (2013)), herein He.
Regarding claim 5, Graeber teaches that the measuring and determining steps include using a binding agent to bind with a mRNA form of each of the biomarkers of each of the biomarkers of the combination of biomarkers, wherein each binding agent is a nucleic acid that hybridizes with the mRNA form of the respective mRNA form of each of the biomarkers; and detecting binding of the binding agent with the mRNA form of each of the biomarkers (“a number of difference[sic] assays could be employed to analyze nucleic acids […] such assays include […] Northern hybridization” [0142]). Evidence that Northern hybridization as taught by Graeber is provided in the reference of He (“after crosslinking the RNA to the membrane, a radiolabeled probe complementary to the gene of interest is hybridized to the immobilized RNA. The solid membrane with the probe specifically bound to the RNA of interest is then dried, exposed, an analyzed. […] it can be a very effective way to detect variant transcripts of genes” page 2, paragraph 1).
It would be obvious to combine Graeber and Lu for the same reasons as discussed in the 35 U.S.C. 103 rejection of claims 1-3 as being unpatentable over Graeber in view of Lu. Therefore, the invention as a whole of claim 5 would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention.
Claims 4, 6-12, and 14-15 are rejected under 35 U.S.C. 103 as being unpatentable over Graeber et al. (US 2022/0244263, effectively filed date 28 May 2019), herein Graeber, in view of Lu et al. (in IDS filed 25 July 2023)(“A two stage ovarian cancer screening strategy using the risk of ovarian cancer algorithm (ROCA) identifies early stage incident cancers and demonstrates high positive predictive value” Cancer 119(19) pages 3454-3461 (2013)), herein Lu, as applied to claims 1-3 above, and further in view of Zhong et al. (US 2019/0310172, published 10 October 2019), herein Zhong.
Regarding claim 4, Graeber teaches that specifically in their scoring of biomarkers for blood cancers and SCN cancer, they find that “protein […] SCN scores are concordant with gene expression SCN scores” [0041]. However, Graeber does not that the measuring and determining steps include using a binding agent to bind with a protein form of each of the biomarkers of the combination of biomarkers; and detecting binding of the binding agent with the protein form of each of the biomarkers. This deficiency is made up for in the teachings of Zhong.
Regarding claim 4, Zhong teaches a method using a binding agent to bind with a protein form and detecting binding of the binding agent with the protein form (“fluorescently labeled binding agent (detection agent) against vesicle antigens of interest” [0039]; FIG. 1A).
Regarding claim 6, Zhong teaches a method of obtaining a diagnosis of cancer (“the biomarkers used to detect a vesicle population can be selected to detect a microvesicle population of interest, e.g., a population of vesicles that provides a diagnosis, prognosis or theranosis of a selected condition or disease, including but not limited to a cancer [0045]), comprising: detecting a panel of extracellular vesicle-associated protein biomarkers in a human subject, comprising: a) obtaining extracellular vesicle-associated proteins from a biological sample from the female human subject (“a method of isolating at least one extracellular vesicle from a sample” [0006]; “analyzing one or more vesicles, such as vesicles, in a biological sample obtained from the subject. A subject or patient can include […] humans” [0115]); b) providing a panel of binding agents to the extracellular vesicle-associated proteins (“aptamer libraries are used as binding agents to characterize the microvesicles” [0037]; “binding agents such as antibodies or aptamers can be used to capture or isolated a component present in a biological sample that has the agent's target molecule present. For example, if a given microvesicle surface antigen is present on a cell, cell fragment or cell-derived extracellular vesicle” [0037]); c) assaying for binding of a plurality of the binding agents of the panel with the plurality of extracellular vesicle-associated proteins; d) detecting binding of the plurality of binding agents of the panel with the plurality of extracellular vesicle-associated proteins (“the captured vesicles are detected using fluorescently labeled binding agent (detection agent) against vesicle antigens of interest” [0039]; FIG. 1A); and e) preparing a report on the detection of binding of the binding agents to the extracellular vesicle-associated proteins (“the biomarkers may be used to identify a biosignature. A “biosignature” as used herein refers to a biomarker profile of a biological sample comprising a presence, level or other characteristic that can be assessed […] of one or more biomarker of interest” [0033] in this case the biosignature or biomarker profile is interpreted as a report).
Regarding claim 6, however, Zhong does not teach that the binding agents are configured to bind with proteins ACSL4, IGSF8, ITGA2, ITGA5, ITGB3, and MYOF. This deficiency is made up for in the teachings of Graeber.
Regarding claim 6, Graeber teaches, as discussed in the 35 U.S.C. 103 rejection of claims 1-3 above, using each of ACSL4, IGSF8, ITGA2, ITGA5, ITGB3, and MYOF as biomarkers for the diagnosis of cancer. Therefore, the combination of Zhong and Graeber teach the entirety of b) providing a panel of binding agents to the extracellular vesicle-associated proteins, wherein the binding agents are configured to bind with extracellular vesicle-associated proteins ACSL4, IGSF8, ITGA2, ITGA5, ITGB3, and MYOF. However, the combination of Zhong and Graeber does not teach providing the report to the subject or to a medical entity or medical practitioner or that the human subject is specifically a female human subject.
Regarding claim 6, Lu teaches, as discussed in the 35 U.S.C. 103 rejection of claims 1-3 above, providing medical reports to subjects/patients, medical entities, and medical practitioners. Lu also teaches using cancer screen assays on human female subjects (“ROCA was originally developed using data from prospective screening trials for postmenopausal women” page 3, paragraph 4).
Regarding claim 7, Zhong teaches that the binding agents are selected from antibodies, aptamers, or combinations thereof (“Binding agents such as antibodies or aptamers can be used to capture or isolated a component present in a biological sample” [0037]).
Regarding claim 8, Graeber teaches, as discussed in the 35 U.S.C. 103 rejection of claims 1-3 above, that the biomarkers include ACSL4, IGSF8, ITGA2, ITGA5, ITGB3, FOLR1, and MYOF, for which the binding agents are selective in the combined method of Graeber, Lu, and Zhong. The phrase “based on higher area under curve (AUC) over a negative control” does not recite either a step of the method or a further limitation to a step or material component of the method. Rather, it states a reason (a higher AUC over a negative control) that a material component (the panel of binding agents) is designed the way it is (being selective for the listed genes). Because this phrase (“based on higher area under curve (AUC) over a negative control”) does not further limit the method by adding a step or limiting a step or material component, it is not interpreted as having patentable weight.
Regarding claim 9, Graeber teaches, as discussed in the 35 U.S.C. 103 rejection of claims 1-3 above, that the biomarkers include ACSL4, IGSF8, ITGA2, ITGA5, ITGB3, MYOF, FOLR1, and STX4, for which the binding agents are selective in the combined method of Graeber, Lu, and Zhong. The phrase “based on higher area under curve (AUC) over a negative control” does not further limit the method by adding a step or limiting a step or material component, so it is not interpreted as having patentable weight (see discussion of claim 8 above).
Regarding claim 10, Zhong teaches that the assaying is a protein binding assay where each binding agent binds with a respective extracellular vesicle-associated protein biomarker from the plurality of extracellular vesicle-associated proteins (“aptamer libraries can also be used to assess levels or presence of their specific target molecule” [0037]).
Regarding claim 11, Zhong teaches that the method may further comprise quantifying levels of the extracellular vesicle-associated protein biomarkers using fluorescence (“A biosignature can be detected qualitatively or quantitatively by detecting a presence, level or concentration of a circulating biomarker, e.g., a microRNA, protein, vesicle or other biomarker […] A biomarker can also be detected by immunoassay, immunoblot, immunoprecipitation, enzyme-linked immunosorbent assay (ELISA; EIA)” [0048]; “FIG. 1A shows an illustrative schematic for a sandwich-type of immunoassay. The capture agent can be against a vesicle antigen of interest, e.g., a general vesicle biomarker, a cell-of-origin marker, or a disease marker. In the figure, the captured vesicles are detected using fluorescently labeled binding agent (detection agent) against vesicle antigens of interest” [0039]; FIG. 1A).
Regarding claim 12, Graeber teaches that expression levels of the sample may be higher than control expression levels (“Some embodiments include determining that a measured expression level is higher than, lower than, increased relative to, decreased relative to, equal to, or within a predetermined amount of a reference expression level” [0138]). Therefore, the combination of Graeber with Zhong and Lu teaches the method of claim 11 wherein levels of the extracellular-vesicle associated protein biomarkers are higher than control (reference) proteins.
Regarding claim 14, Zhong teaches a method further comprising applying secondary antibodies conjugated to biotin to the binding agents and bound extracellular vesicle-associated protein biomarkers, which are used as fluorescent reporters (“A binding agent can be directly or indirectly labeled, e.g., the label is attached to the antibody through biotin-streptavidin. Alternatively, an antibody is not labeled, but is later contacted with a second antibody that is labeled after the first antibody is bound to an antigen of interest” [0206] this teaches that a secondary antibody may be labeled by having a label attached to it via biotin; “a detectable label, here a fluorescent signal” [0019]).
Regarding claim 15, Lu teaches, as discussed in the 35 U.S.C. 103 rejection of claims 1-3 above, that the report may include a listing of medical entities that perform, oversee, or control the treatments for ovarian cancer (“referral to a gynecologic oncologist” page 4, paragraph 1).
It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to perform the simple substitution of the protein detection method taught by Zhong with the nucleic acid detection step in the method taught by Graeber in view of Lu. Though transcript and protein expression cannot be assumed to be concordant (see discussion of Chan in the 35 U.S.C. 112(a) scope of enablement rejection of claims 1-5), Graeber teaches that for the purpose of diagnosing SCN cancer, the SCN scores of protein and gene expression are concordant. Therefore, one of ordinary skill in the art would have a reasonable expectation that the results of substituting the protein detection taught by Zhong for the nucleic acid detection in the method of diagnosing cancer of Graeber in view of Lu would be predictable. Therefore, the invention as a whole of claims 4, 6-12, and 14-15 would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention.
Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over Graeber et al. (US 2022/0244263, effectively filed date 28 May 2019), herein Graeber, in view of Lu et al. (in IDS filed 25 July 2023)(“A two stage ovarian cancer screening strategy using the risk of ovarian cancer algorithm (ROCA) identifies early stage incident cancers and demonstrates high positive predictive value” Cancer 119(19) pages 3454-3461 (2013)), herein Lu, and in view of Zhong et al. (US 2019/0310172, published 10 October 2019), herein Zhong, as applied to claims 4, 6-12, and 14-15 above, and as evidenced by Seo et al. (“Mechanism for survival of homozygous nonsense mutations in the tumor suppressor gene BRCA1” Proc Natl Acad Sci U S A 115(20) pages 5241-5246 (2018)), herein Seo.
Regarding claim 13, the combination of Graeber, Lu, and Zhong teach the method of claim 6, as discussed in the 35 U.S.C. 103 rejection of claims 4, 6-12, and 14-15 above, comprising selecting the female human subject by being positive for BRCA1 because the method uses a female human subject. Seo provides evidence that all possible female human subjects are positive for BRCA1 (“BRCA1 is essential for repair of DNA double-strand breaks by homologous recombination, and hence for survival. Complete loss of its function is lethal during early embryonic development” Abstract).
It would be obvious to combine Graeber, Lu, and Zhong for the same reasons as discussed in the 35 U.S.C. 103 rejection of claims 4, 6-12, and 13-15 as being unpatentable over Graeber in view of Lu and further in view of Zhong. Therefore, the invention as a whole of claim 13 would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention.
Rejected Claims Free of the Prior Art
Claims 18-24 are free of the prior art. Claim 18 is free of the prior art specifically because it recites “the report has an identification of […] IGSF8 […] as biomarkers of ovarian cancer” and the prior art does not teach IGSF8 as a biomarker of ovarian cancer. Claims 19-24 are free of the prior art by virtue of their dependency on claim 18. However, claims 18-24 still stand rejected under 35 U.S.C. 101 for not being patentable subject matter, 35 U.S.C. 112(a) for not enabling the full scope of the claims, and 35 U.S.C. 112(b) for indefiniteness and claims 20, 22, and 24 additionally stand rejected under 35. U.S.C. 112(d) for failure to limit the claims on which they depend.
Conclusion
Claims 1-15 and 18-24 are rejected. Claims 16-17 are withdrawn.
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/JEFFREY BELLAH/Examiner, Art Unit 1683
/ANNE M. GUSSOW/Supervisory Patent Examiner, Art Unit 1683