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
Acknowledgment is made of the present application as a proper National Stage (371) entry of PCT Application No. PCT/US2021041604, filed 07/14/2021, which claims benefit under 35 U.S.C. 119(e) to provisional application No. 63/051,882, filed 07/14/2020.
Information Disclosure Statement
The information disclosure statement (IDS) filed 01/17/2023 has been considered, initialed and is attached hereto.
Status of the Claims
Claims 1-4, 8-11, 15-17, 19, 23, 27, and 30-32 are pending in the application. Claims 4, 10-11, 17, 19, 23, and 27 are amended. Claims 1-4, 8-11, 15-17, 19, 23, 27, and 30-32 are examined below.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 27 and 30-31 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 detecting B-cell like neutrophils (“BNeuts”) comprising obtaining a biological sample from a subject; and detecting whether BNeuts are present or increased in the biological sample by contacting the biological sample with an agent capable of detecting CD3-CD56-CD79b+CD66b+PAX5+CD19- cells, CD3-CD56- CD79a+CD79b+CD66b+PAX5+CD19- cells, or both, and detecting the increase of BNeuts in the biological sample, the specification does not reasonably provide enablement for adoptive cell therapy that comprises BNeuts (CD3-CD56-CD79b+CD66b+PAX5+CD19- cells, CD3-CD56- CD79a+CD79b+CD66b+PAX5+CD19- cells, or both) and growing BNeuts (CD3-CD56-CD79b+CD66b+PAX5+CD19- cells, CD3-CD56- CD79a+CD79b+CD66b+PAX5+CD19- cells, or both) (claim 30) ex vivo. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make or use the invention commensurate in scope with these claims.
The factors considered when determining if the disclosure satisfies the enablement requirement and whether any necessary experimentation is "undue" include, but are not limited to: 1) nature of the invention, 2) state of the prior art, 3) relative skill of those in the art, 4) level of predictability in the art, 5) existence of working examples, 6) breadth of claims, 7) amount of direction or guidance by the inventor, and 8) quantity of experimentation needed to make or use the invention. In re Wands, 858 F.2d 731,737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
The nature of the invention relates to a method of detecting BNeuts (CD3-CD56-CD79b+CD66b+PAX5+CD19- cells, CD3-CD56- CD79a+CD79b+CD66b+PAX5+CD19- cells) in a biological sample of a subject and if the patient has or has an increase in BNeuts, then providing an adoptive cell therapy that comprises BNeuts (claim 27) comprising the step of isolating BNeuts from a patient, growing the BNeuts ex vivo and isolating the BNeuts prior to the adoptive cell therapy (claim 30).
Zhang et al. (Challenges and new technologies in adoptive cell therapy. Journal of Hematology & Oncology. 2023 Aug 18;16(1):97) teaches that adoptive cell therapy is an active biological strategy that employs “live” drugs, whereby patient immune cells are collected before being reinfused into the patient’s body to kill pathogens and/or cancer cells (Zhang, page 1 of 55, 2nd paragraph, lines 4-8). Put another way, Zhang teaches that adoptive cell therapy requires live cells.
It has been well established in the art that cellular surface markers can be used to isolate live cell populations identified by a specific combination of cell surface markers from the biological sample of a subject, also called cell sorting.
For example, Mattanovich (Mattanovich et al. Applications of cell sorting in biotechnology. Microbial Cell Factories. 2006;5(1):12), teaches that the term cell sorting can be used for any technique that separates cells according to their properties including panning, fluorescence activated cell sorting, magnetic cell sorting, or newer techniques such as dielectrophoresis involving microfluidic devices (Mattanovich, page 2 of 11, 2nd paragraph, lines 1-6). Mattanovich further teaches that both panning and magnetic cell sorting can be used for the selection of cells according to the expression of surface molecules, because only such surface expressed molecules can be detected by these techniques. Mattanovich further teaches that both methods are bulk methods that allow rapid isolation of a large number of cells and that flow cytometry is the only method that allows both single cell selection as well as a relative quantification of a specific compound and desirable cells can be isolated quickly and efficiently. Mattanovich further teaches that intracellular markers such as green fluorescent protein can be measured and used for sorting by flow cytometry (Mattanovich, page 3 of 11, 1st paragraph, lines 1-19). See also Tomlinson (Tomlinson et al. Cell separation: Terminology and practical considerations. Journal of tissue engineering. 2013;4:2041731412472690) teaches that there are a number of techniques using antibodies for cell separation, including fluorescence activated cell sorting, magnetic cell sorting, columns with antibody-immobilized surfaces, and polymer cryogels. Other techniques include magnetophoresis, DNA aptamer binding, and aqueous phase partitioning (Tomlinson, page 4, see entire 3rd paragraph). Tomlinson further teaches that there are still some problems, specifically with flow cytometry and magnetic cell sorting, such as the reliance on cell surface markers (Tomlinson, page 5, 4th paragraph, lines 4-6). Further, “The complete flow cytometry guide” (The complete flow cytometry guide 2023 https://www.abcam.com/en-us/technical-resources/guides/flow-cytometry-guide/fluorescence-activated-cell-sorting-live-cells accessed/downloaded 12/29/2025) teaches that performing intracellular staining before sorting live cells is usually not possible as permeabilization requires damaging the cell membrane, which would compromise cell viability (Abcam: The complete flow cytometry guide, page 26, lines 12-13). Put another way, the prior art teaches that living cells can be isolated based on cell surface markers, but that sorting cells by intracellular markers requires the cells to be permeabilized and it is therefore not possible to sort live cells based on intracellular markers.
Furthermore, regarding the prior art, Meyer (Meyer et al. Human CD79b+ neutrophils in the blood are associated with early-stage melanoma. Frontiers in immunology. 2023 Oct 31;14:1224045) teaches identifying CD79b+ neutrophils by expression level of several cell surface markers (CD3-CD56-CD19-Siglec8-CD203c-CD86loCD66b+CD79b+; Meyer, page 1, ‘Results’, lines 1-2). Meyer further teaches sorting CD79b+ neutrophils (Meyer, page 9, 2nd paragraph, lines 1-6). Meyer further teaches that the CD79b+ neutrophils express PAX5 (Meyer, page 9, 2nd column, 2nd paragraph, lines 20-21) and that PAX5 is a transcription factor (Meyer, page 12, 3rd paragraph, lines 13-15).
Desouki et al. (PAX-5: a valuable immunohistochemical marker in the differential diagnosis of lymphoid neoplasms. Clinical medicine & research. 2010 Jul 26;8(2):84-8) teaches that PAX-5 is expressed in the nucleus (Desouki, page 85, 2nd paragraph, lines 1-2, and Figure 1).
The specification recites that the method further comprises the step of isolating BNeuts from the cancer patient, growing the BNeuts ex vivo, and isolating the BNeuts prior to the adoptive cell therapy (Specification, page 3, see entire paragraph [0018]).
Although it is predictable that live B cell like neutrophils expressing CD3-CD56-CD19-Siglec8-CD203c-CD86loCD66b+CD79b+ surface markers can be sorted by cell sorting methods involving antibodies, such as fluorescent activated cell sorting or magnetic cell sorting, it is not readily predictable that BNeuts expressing CD3-CD56-CD79b+CD66b+PAX5+CD19- cells or CD3-CD56- CD79a+CD79b+CD66b+PAX5+CD19- cells can be sorted for adoptive cell therapy or expansion ex vivo, which requires live cells, because the prior art states that labeling intracellular markers requires damaging the cell membrane which compromises cell viability. One of ordinary skill in the art would not be expected to be able to sort cells for adoptive cell therapy or expansion ex vivo, i.e. live cells, based on the expression levels of CD3-CD56-CD79b+CD66b+PAX5+CD19- cells or CD3-CD56- CD79a+CD79b+CD66b+PAX5+CD19- because PAX5 is a transcription factor expressed in the nucleus and in order to label cells with a PAX5-specific binding agents cells would have to be permeabilized and would no longer be viable.
The originally filed specification lacks any working examples demonstrating the ability to isolate live BNeuts based on the expression of CD3-CD56-CD79b+CD66b+PAX5+CD19- cells or CD3-CD56- CD79a+CD79b+CD66b+PAX5+CD19-. At page 5, lines 5-9, the originally filed specification indicates that BNeuts were isolated from melanoma patient blood and loaded with MHCII restricted viral peptides and that after co-culture with healthy donor T cells and CD4 T cells’ IFNγ expression was measured by flow cytometry.
Regarding the breadth of the claims, the claims recite “providing an adoptive cell therapy that comprises BNeuts, CD3-CD56-CD79b+CD66b+PAX5+CD19- cells or CD3-CD56-CD79a+CD79b+CD66b+PAX5+ CD19- cells, or any combination thereof, to the patient in an amount sufficient to reduce or treat the cancer.” And “comprising the step of isolating BNeuts from the cancer patient, growing the BNeuts ex vivo, and isolating the BNeuts prior to the adoptive cell therapy’. The claims are not specific to any particular method of isolating the BNeuts.
The specification lacks guidance regarding how to isolate CD3-CD56-CD79b+CD66b+PAX5+CD19- cells or CD3-CD56-CD79a+CD79b+CD66b+PAX5+ CD19- cells. The specification lacks a working example for isolating the cells from a sample and further lacks description of the biomarkers used for isolation/sorting. It further fails to recite whether the method involved labeling only extracellular or also intracellular markers in the live cells and how that can be achieved considering that intracellular staining affects the viability of the cells. Finally, the originally filed specification lacks support for the expression of PAX5 in all BNeuts and as such one cannot isolate BNeuts without labeling PAX5, i.e. without labeling an intracellular marker, to ascertain that the cell population expresses all the claimed markers CD3-CD56-D79b+CD66b+PAX5+CD19- or CD3-CD56- CD79a+CD79b+CD66b+PAX5+CD19-.
The skill level of those skilled in the art is high and since the art teaches various methods of isolating or sorting live cells by labelling extracellular, but not intracellular markers, the unpredictability in the art that an intracellular marker could be used to isolate live cells for adoptive cell therapy or expansion ex vivo as claimed, the lack of working examples, breadth of the claims, and the lack of direction and guidance, the specification fails to teach the skilled artisan how to make or use the claimed invention without undue experimentation.
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 4, 8-11, 15-17, 19, 23, 27, and 30-31 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.
Regarding claim 4, the claim recites “the cancer is selected from a colorectal […] cancer issue”. It is further unclear what is meant by a “cancer issue” and the specification, though it does recite “cancer issue”, it does not provide an explanation as to the meaning of the phrase.
Regarding claim 27, the claim recites administering BNeuts in “an amount sufficient to reduce or treat cancer”. The recited language suggests limitations to the amount of BNeuts administered, described in terms of the use of the cells but places no clear limitation on the amount itself. Because one cannot readily visualize what amount of cells the claimed method is limited to, the claim is considered indefinite.
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 1-4, 8-11, 15-17, 19, and 23are rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter, abstract ideas (i.e., mental concept) and a natural correlation without significantly more.
The U.S. Patent and Trademark Office recently revised the MPEP with regard to § 101 (see the MPEP at 2106). Regarding the MPEP at 2106, in determining what concept the claim is “directed to”, we first look to whether the claim recites:
any judicial exceptions, including certain groupings of abstract ideas (i.e., mathematical concepts, certain methods of organizing human activity such as a fundamental economic practice, or mental processes); and
additional elements that integrate the judicial exception into a practical application (see MPEP § 2106.05(a)-(c), (e)-(h)).
Only if a claim (1) recites a judicial exception and (2) does not integrate that exception into a practical application, do we then look to whether the claim contains an “’inventive concept’ sufficient to ‘transform’” the claimed judicial exception into a patent -eligible application of the judicial exception. Alice, 573, U.S. at 221 (quoting Mayo, 566 U.S. at 82). In so doing, we thus consider whether the claim:
adds a specific limitation beyond the judicial exception that is no “well-understood, routine, conventional: in the field (see MPEP § 2106.05(d)); or
simply appends well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception.
See MPEP 2106.
ELIGIBILITY STEP 2A: WHETHER A CLAIM IS DIRECTED TO A JUDICIAL EXCEPTION
Step 2A, prong 1
Claim 1 recites “detecting whether BNeuts are present or increased”, claim 2 recites “detecting […] an elevated level of expression”, claim 8 recites “when compared to an amount of BNeuts in a healthy patient”; claim 10 recites “diagnosing and treating a cancer in a patient […] identifying that the patient has a presence or an increase in BNeuts when compared to a reference level generated form a healthy patient”; claim 16 recites “determining whether the patient has B-cell like neutrophils (BNeut) or an increase in BNeuts, when compared to a reference level”. The steps of comparing (claims 1, 2, and 10: detecting whether BNeuts are increased and detecting an elevated level comprises comparing the levels to relative to a standard or reference level; claims 8: compared to) and diagnosing (claim 10) are categorized as abstract ideas, namely each are a mental process/ concept performed in the human mind. For example “diagnosing […] a cancer in a patient […] increase in BNeuts when compared to a reference level” encompasses a practitioner simply observing the results and thinking about the quantified amount relative to a healthy patient and making an evaluation, judgement or opinion. The claims under broadest reasonable interpretation, cover performance of these steps solely within the human mind. The step of comparing the BNeuts to a reference level or to a healthy patient is an abstract idea; comparing measured levels to a cutoff/threshold value is insufficient to integrate into practical application because comparing information regarding a sample or test subject to a control or target data has been held to be an "abstract mental process" (see as in University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 113 USPQ2d 1241 (Fed. Cir. 2014) which involved "comparing BRCA sequences and determining the existence of alterations", the collecting and comparing of known information in Classen, the comparing information regarding a sample or test subject to a control or target data in Ambry and Myriad CAFC, as well as Mayo, which also involved specific numerical cutoff levels). The recitation of identifying a cancer patient due to the presence or increase of BNeuts is directed to the natural correlation between the presence or increase of BNeuts in the sample and the subject suffering from cancer. This natural relationship is a law of nature. Similar concepts have been held by the courts to constitute law of nature/ natural phenomena, as in the identification of a correlation between the presence of myeloperoxidase in a bodily sample (such as blood or plasma) and cardiovascular disease risk in Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1361, 123 USPQ2d 1081, 1087 (Fed. Cir. 2017). In Mayo, the Supreme Court found that a claim was directed to a natural law, where the claim required administering a drug and determining the levels of a metabolite following administration, where the level of metabolite was indicative of a need to increase or decrease the dosage of the drug. See Mayo Collaborative Services v. Prometheus Labs., Inc., 566 U.S. 66, 74 (2012).
The instant claims are similar to those as in Mayo as they involve a "relation itself [which] exists in principle apart from any human action" (id. at 77), namely the relationship between the naturally occurring presence or increase of BNeuts and cancer.
The correlation as indicated is a judicial exception as it exists in principle apart from any human action; the correlation itself therefore cannot form the basis for eligibility.
Step 2A, prong 1
The above-discussed steps of comparing and diagnosing are steps insufficient to constitute a practical application. In this case, the comparing and diagnosing represent judicial exceptions and not a practical application thereof.
In addition to the judicial exceptions, claim 3 further recites that the step of detecting is “measuring mRNA, protein, or both”, claim 4 recites that the “biological sample is a blood sample”, claim 15 recites the additional “markers: CD40, CD80, CD86, or HLA-DR”; Claims 10 and 16 similarly cite additional steps of “Obtaining or having obtained a biological sample from the patient; performing or having performed an assay on the biological sample to determine an amount of BNeuts”; and dependent claims 11, 17 and 15, 19 recite “the step of detecting is measuring mRNA, protein, or both” and “detecting if the BNeuts express one or more of the following markers: CD40, CD80, CD86, or HLA-DR”. Such steps of detecting BNeuts in a sample is insufficient to integrate the judicial exception because the purpose is merely to obtain data. This does not go beyond insignificant presolution activity, i.e., a mere data gathering step necessary to use the correlation, similar to the fact pattern in In re Grams, 888 F.2d 835 (Fed.Cir. 1989) and Ariosa Diagnostics, Inc v. Sequenom, Inc. (Fed. Cir. 2015). Furthermore, the step of BNeuts is recited at a high level of generality (claims 11 and 17 “the step of detecting is measuring mRNA, protein, or both”) and is not tied, for example, to any particular machine or apparatus. The courts have recognized determining the level of a biomarker in blood by any means as well-understood, routine, conventional activity in the life science arts when they are claimed in a merely generic manner (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).
Although the claims recite a particular treatment, namely “administering a cancer treatment or therapy to the patient” (claims 10 and 16), “providing an adoptive cell therapy” (claim 27), the treatment is applied “if the patient has BNeuts” (claims 10 and 16). As such, the treatment is recited as conditional (“if the patient has”) and therefore encompasses doing nothing, for example not treating the subject. Therefore, the claims encompass doing noting when given broadest reasonable interpretation.
ELIGIBILTIY STEP 2B: WHETHER THE ADDITIONAL ELEMENTS CONTRIBUTE AN “INVENTIVE CONCEPT”
The additional elements (in addition to the judicial exceptions noted above) of the claims, including the steps of obtaining a sample and detecting the BNeuts, do not add more to the judicial exceptions. The step of detecting whether BNeuts are present or increased is recited at a high level of generality and is not limited, for example, to any specific testing technique, see claims 11 and 17 recite “the step of detecting is measuring mRNA, protein, or both”. Furthermore, the specification supports the routine and conventional nature of the claimed detection step, see as the specification indicates that the method of detecting BNeuts is by flow cytometry (see for example page 16, paragraph [0087] of the specification).
In this case it was well-understood, routine and conventional to determine cell types in a sample by flow cytometry or by measuring gene expression, including combining different combinations of cell surface or intracellular markers such as CD3, CD56, CD79a, CD79b, CD66b, PAX5, and CD19. See for example, Doherty et al. (STAT6 regulates natural helper cell proliferation during lung inflammation initiated by Alternaria. American Journal of Physiology-Lung Cellular and Molecular Physiology. 2012 Oct 1) teaches detecting an innate lymphoid cell type that do not express known lineage markers, such as CD3, CD4, CD8, CD5, CD19, GR-1, CD11c, NK1.1 and others (Doherty, page L577, 2nd column, 3rd paragraph, lines 3-5). Doherty teaches incubating human peripheral blood mononuclear cells with a combination comprising human lineage cocktail followed by intracellular staining for transcription factors ETS-1 and GATAA-3 staining (Doherty, page L578, 2nd column, lines 27-32). Serr et al. (Type 1 diabetes vaccine candidates promote human Foxp3+ Treg induction in humanized mice. Nature communications. 2016 Mar 15;7(1):10991) similarly teaches staining cells with an anti-lineage cocktail comprising (CD3, CD14, CD16, CD19, CD20, and CD56; Serr, page 14, ‘Cell staining for flow cytometry and cell sorting’, 2nd paragraph, lines 10-11) and further teaches that after surface staining, cells were fixed and permeabilized and intracellular transcription factor Foxp3 expression was detected (Serr, page 14, ‘Cell staining for flow cytometry and cell sorting’, 3rd paragraph, lines1-2). Zwollo et al. (Comparative analyses of B cell populations in trout kidney and mouse bone marrow: establishing “B cell signatures”. Developmental & Comparative Immunology. 2010 Dec 1;34(12):1291-9) teaches detecting B220 and CD43 in combination with Pax5 on mouse bone marrow cells by flow cytometry (Zwollo, page 1295, see figure 3). Zwollo further teaches that Pax5 is a transcription factor (Zwollo, page 1291, 2nd column, 3rd paragraph, lines 1-2). Moore et al. (Innate immune cell signatures in a BCWD-Resistant line of rainbow trout before and after in vivo challenge with Flavobacterium psychrophilum. Developmental & Comparative Immunology. 2019 Jan 1;90:47-54) teaches using a trout-specific monoclonal antibody named QE4 which recognizes neutrophil-like cells (Moore, page 47, 2nd paragraph, lines 2-3) and Pax5 specific antibody in flow cytometry (Moore, page 49, ‘3.2. Identification of myeloid/granulocytic cell populations using flow cytometry’, 5th paragraph, lines 1-2) to examine PAX5 and/or QE4 positive cell populations (Moore, page 50, see figure 2). Summers et al. (Phenotypic characterization of five dendritic cell subsets in human tonsils. The American journal of pathology. 2001 Jul 1;159(1):285-95) teaches identifying HLA-DR, CD11c, CD13, and CD123 dendritic cell subsets by flow cytometry and assessing differential expression of co-stimulatory molecules including CD86 (Summers, Abstract, lines 14-21), as well as staining with antibodies against CD3, CD19, CD40, CD79a, CD79b, and CD80 (Summers, page 287, see table 1) and further teaches identifying different populations by co-expression or lack of said markers (see table 2 and page 288, ‘T cell, B cell, and myeloid antigens’, lines 1-7). Carrasco et al. (CD66 expression in acute leukaemia. Annals of hematology. 2000 Jun;79(6):299-303) teaches identifying cells by flow cytometry using different combinations of cell surface markers comprising CD66, CD79a, CD19, and CD3 (Carrasco, page 300, ‘Sample preparation’, see entire 1st paragraph). Witkowski et al. (Extensive remodeling of the immune microenvironment in B cell acute lymphoblastic leukemia. Cancer cell. 2020 Jun 8;37(6):867-82; see also below in the rejection under 35 U.S.C. 103) teaches CITE-seq to simultaneously characterize single-cell transcriptome and cell surface protein composition using an immune system specific oligonucleotide-labeled CITE-seq antibody panel (Witkowski, page 872, 2nd column, 2nd paragraph, lines 1-8) comprising CD3, CD19, CD56, CD66b, and HLA-DR (Witkowski, pages e2-e4, key resources table) and detecting gene expression of CD79 and Pax5 (Witkowski, Figure S1 D).
In view of the above evidence, namely that it was well-understood, routine, and conventional to detect cell populations by using different combinations of known cell markers, extracellular as well as intracellular (such as transcription factors) including different combinations of the markers as claimed, the claimed steps of detecting BNeuts in a sample by adding labels for CD3, CD56, CD79a, CD79b, CD66b, PAX5, and CD19, does not add any feature that is more than well-understood, routine and conventional in the field of diagnostics and biochemical assay methodologies.
When recited at this high level of generality, there is no meaningful limitation, such as a particular or unconventional machine or a transformation of a particular article, in this step that distinguishes it from well-understood, routine, and conventional data gathering activity engaged in by scientists prior to applicant's invention, and at the time the application was filed, e.g., the routine and conventional techniques of detecting a protein in blood. See also MPEP 2106.0S(g).
Although the limitations of claims 10, 16, and 27 are directed to very specific and particular treatment, for the reasons as indicated previously above, the claims do not clearly require the treatment to be administered and rather instead encompass instances that amount to taking no action.
For all these reasons, the claims fail to include additional elements that are sufficient to amount to significantly more than the judicial exception.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (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 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 1-4, 8-11, 15-17, 19, and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Luger et al. Expression of the B-cell receptor component CD79 on immature myeloid cells contributes to their tumor promoting effects. PLoS One. 2013 Oct 16;8(10):e76115, in view of Witkowski et al. Extensive remodeling of the immune microenvironment in B cell acute lymphoblastic leukemia. Cancer cell. 2020 Jun 8;37(6):867-82, as evidenced by Janeway et al. The components of the immune system. In Immunobiology: The Immune System in Health and Disease. 5th edition 2001, Chapter 1, pages 1-6. Garland Science.
Regarding claim 1, Luger teaches the existence of cancer-induced myeloid-derived suppressor cells which are of myeloid origin and immature phenotype and have a close relationship with immature myeloid cells that exist in the normal bone marrow. Luger further teaches that said cells are phenotypically diverse, which many different subpopulations expressing different combinations of cell surface markers depending on the cancer type and stage, such as granulocytic and monocytic myeloid suppressor cells (Luger, page 1 of 19, 2nd paragraph, lines 1-14). According to Janeway, granulocytes are a type of myeloid cells which comprise neutrophils and neutrophils are the most numerous cellular component of the innate immune response (Janeway, page 1, ‘Myeloid progenitor’, see entire 1st paragraph and 3rd paragraph-page 2, lines -4). Luger further teaches staining mouse cells with various surface marker antibodies such as CD11b, Gr1, IgM, CD19, B110, Ly6C, Ly6G, f4/80, and anti-CD79a and CD79b (Luger, page 16 of 19, ‘Flow cytometry and FACS sorting’, see entire 1st paragraph). Luger further teaches that the B cell receptor subunit CD79a is expressed on peripheral myeloid-derived suppressor cells that are expanded by metastatic tumors in a number of mouse tumor models (Luger, page 3 of 19, 2nd column, ‘The B cell receptor subunit CD79a is expressed on the MDSC population that is expanded by metastatic tumors’). Luger further teaches that the mouse myeloid derived suppressor cells have markers that reflect their immature status and have a close relationship to the immature myeloid cells that exist in bone marrow (Luger, page 1 of 19, 2nd paragraph, lines 5-8). Luger teaches a method of detecting mouse myeloid-derived suppressor cells using CD11b, Gr1, and CD79b by flow cytometry (Luger, page 16 of 19, 2nd column, 2nd paragraph, lines 8-11). Luger teaches that CD79 is expressed on naïve immature bone marrow myeloid cells and on myeloid-derived suppressor cells in tumor-bearing animals. Luger further teaches tumor-induced CD79a expression on myeloid-derived suppressor cells was also observed in human cancer patients suggesting that CD79 on said cells may be a novel target for cancer therapy (Luger, page e76115, 3rd paragraph, lines 11-20). Luger further teaches that CD79 is found on normal human immature bone marrow myeloid cells and upregulated on peripheral myeloid-derived suppressor cells from cancer patients (Luger, page 11, 2nd column, 2nd paragraph, lines 1-5). Luger further teaches that one widely used marker used to identify human myeloid-derived suppressor cells is a combination of being Lineage negative (CD3-, CD56-,CD19-), HLA-DR-, CD11b+, and CD33+).
As such Luger teaches detecting a cell population of myeloid derived suppressor cells that comprises neutrophils and expresses a B cell receptor component and as such teaches detecting a population of cells that is increased in the periphery in cancer and comprises a B cell-like neutrophil, or BNeut and has a close relationship with immature bone marrow myeloid cells.
Luger does not teach detecting a B-cell like neutrophil by contacting the sample with agents capable of detecting CD3, CD56, CD79a, CD79b, CD66b, PAX5, and CD19.
Witkowski teaches single cell proteomics in bone marrow and peripheral blood of leukemia patients using CITE-seq which allows for simultaneous characterization of single-cell transcriptome and cell surface protein composition. Witkowski teaches using an immune system specific oligonucleotide-labeled CITE-seq antibody panel (Witkowski, page 872, 2nd column, 2nd paragraph, lines 1-8) and tagging peripheral blood samples with cell hashing oligo-tagged antibodies (contacting the sample with agents capable of detecting; Witkowski, page e7, 5th paragraph, lines 7-8). Witkowski further teaches that the CITE-seq antibody panel comprises CD3, CD19, CD56, CD66b, and HLA-DR (Witkowski, pages e2-e4, key resources table). Witkowski further teaches obtaining cryopreserved bone marrow and peripheral blood samples from pediatric cancer patients (obtaining a biological sample; Witkowski, e6, ‘Human Patient Samples’, lines 1-5). Witkowski further teaches detecting gene expression of CD79 and Pax5 (Witkowski, Figure S1 D). Witkowski teaches that CITE-seq allows for simultaneous characterization of single cell transcriptome and cell surface proteins and as such teaches a method of measuring the expression level of CD79 and Pax5 on single cells that can also be labeled with CD3, CD19, CD56, CD66b, and HLA-DR.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Luger with the detection agents of Witkowski comprising CITE-seq antibody panel comprises CD3, CD19, CD56, CD66b, and HLA-DR and detecting gene expression of CD79 and PAX5 because it would necessarily result in the detection of BNeuts comprised in the myeloid derived suppressor cells as described by Luger. Luger describes a cell population comprising neutrophils that expresses a B cell receptor component that is found in the periphery of mice in mouse cancer models and Witkowski describes a method of single cell assessment comprising the markers of BNeuts as claimed in the periphery of patients suffering from cancer. The ordinary artisan would be motivated to evaluate the CD79 expressing myeloid suppressor cells (as described by Luger in mice that would be necessarily detected by the method of Witkowski in human cancer patients because Witkowski teaches a method of detecting cell populations in human cancer patients using the markers as claimed) because of the teaching of Luger that CD79 on myeloid suppressor cells may be a novel target for cancer therapy in humans.
Regarding claim 2, Luger and the cited art above as applied to claim 1 also applies to claim 2.
Witkowski teaches using an immune system specific oligonucleotide-labeled CITE-seq antibody panel (Witkowski, page 872, 2nd column, 2nd paragraph, lines 1-8). Witkowski further teaches that the CITE-seq antibody panel comprises CD3, CD19, CD56, CD66b, and HLA-DR (Witkowski, pages e2-e4, key resources table).
Regarding claim 3, Luger and the cited art above as applied to claim 1 also applies to claim 3.
Witkowski teaches using CITE-seq, which allows for simultaneous characterization of single-cell transcriptome and cell surface protein composition (Witkowski, page 872, 2nd column, 2nd paragraph, lines 4-6). Put another way, Witkowski is teaching a step of detecting protein.
Regarding claim 4, Luger and the cited art above as applied to claim 1 also applies to claim 4.
Witkowski further teaches obtaining cryopreserved bone marrow and peripheral blood samples from pediatric cancer patients (blood sample from a subject having cancer; Witkowski, e6, ‘Human Patient Samples’, lines 1-5).
Regarding claim 8, Luger teaches comparing the proportion of CD79+ expressing myeloid-derived suppressor cells relative to total myeloid-derived suppressor cells between normal donors and cancer patients (Luger, page 14, figure 8 D).
Regarding claim 9, Luger and the cited art above as applied to claim 1 also applies to claim 9.
Witkowski teaches tagging peripheral blood samples with cell hashing oligo-tagged antibodies (agent is an antibody; Witkowski, page e7, 5th paragraph, lines 7-8).
Regarding claim 10, Luger teaches testing blood from human lung cancer patients and that all patients were receiving standard of care treatment (Luger, page 16, 2nd paragraph, lines 4-11). Luger teaches comparing the proportion of CD79+ expressing myeloid-derived suppressor cells relative to total myeloid-derived suppressor cells between normal donors and cancer patients and further shows an increase in CD79+ expressing myeloid-derived suppressor cells comprising BNeuts in cancer patients compared to normal controls (Luger, page 14, figure 8D). As such Luger teaches that cancer patients can be identified by an increase in CD79+ expressing myeloid-derived suppressor cells.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have used the method of Luger to identify patients with cancer and administer cancer treatment to patients with increased CD79+ expressing myeloid-derived suppressor cells because of the teaching of Luger that an increase in said cells identifies people suffering from cancer. The ordinary artisan would be motivated to treat patients identified in such a way because all patients in the group that were suffering from cancer and had increased levels of CD79+ expressing myeloid-derived suppressor cells comprising BNeuts were receiving treatment. Put another way, the increase in CD79+ expressing myeloid-derived suppressor cells comprising BNeuts identifies patients in need of treatment.
Regarding claim 11, Luger and the cited art above as applied to claim 1 also applies to claim 11.
Witkowski teaches using CITE-seq, which allows for simultaneous characterization of single-cell transcriptome and cell surface protein composition (Witkowski, page 872, 2nd column, 2nd paragraph, lines 4-6). Put another way, Witkowski is teaching a step of detecting protein.
Regarding claim 15, Luger and the cited art above as applied to claim 1 also applies to claim 15.
Witkowski teaches using an immune system specific oligonucleotide-labeled CITE-seq antibody panel (Witkowski, page 872, 2nd column, 2nd paragraph, lines 1-8). Witkowski further teaches that the CITE-seq antibody panel comprises CD3, CD19, CD56, CD66b, and HLA-DR (Witkowski, pages e2-e4, key resources table).
Regarding claims 16 and 19, as explained previously in detail above, Luger and the cited art above teach a method of treating a patient suffering from cancer by determining whether the patient has an increase in CD3-CD56-D79b+CD66b+PAX5+CD19- BNeut or CD79+ expressing myeloid-derived suppressor cells comprising BNeuts.
Regarding claim 17, Luger and the cited art above as applied to claim 16 also applies to claim 17.
Witkowski teaches using CITE-seq, which allows for simultaneous characterization of single-cell transcriptome and cell surface protein composition (Witkowski, page 872, 2nd column, 2nd paragraph, lines 4-6). Put another way, Witkowski is teaching a step of detecting protein. Witkowski further teaches tagging peripheral blood samples with cell hashing oligo-tagged antibodies (agent is an antibody; Witkowski, page e7, 5th paragraph, lines 7-8).
Regarding claim 23, Luger and the cited art above teaches a method of identifying a population of myeloid derived suppressor cells comprising BNeuts.
As discussed previously in detail above it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have used the method of Luger to identify patients with cancer and administer cancer treatment to patients with increased CD79+ expressing myeloid-derived suppressor cells comprising BNeuts for the reasons discussed above. It would have further been obvious to treat the patients with chemotherapy because the patients were in need of chemotherapy.
Claim 32 are rejected under 35 U.S.C. 103 as being unpatentable over Witkowski et al., in view of Zuk et al. US 4,208,479, 06/17/1980.
Regarding claim 32, Witkowski teaches using an immune system specific oligonucleotide-labeled CITE-seq antibody panel (Witkowski, page 872, 2nd column, 2nd paragraph, lines 1-8) and tagging peripheral blood samples with cell hashing oligo-tagged antibodies (contacting the sample with agents capable of detecting; Witkowski, page e7, 5th paragraph, lines 7-8). Witkowski further teaches that the CITE-seq antibody panel comprises CD3, CD19, CD56, CD66b, and HLA-DR (Witkowski, pages e2-e4, key resources table). Witkowski further teaches obtaining cryopreserved bone marrow and peripheral blood samples from pediatric cancer patients (obtaining a biological sample; Witkowski, e6, ‘Human Patient Samples’, lines 1-5). Witkowski further teaches detecting gene expression of CD79 and Pax5 (Witkowski, Figure S1 D).
The advantages of packaging together the necessary reagents in kit form were well known in the art at the time of the invention. For example, Zuk et al. teach that in performing assays it is a matter of substantial convenience, as well as providing significant enhancement in accuracy, to provide the reagents combined in a kit (column 22, lines 20-68).
Although Witkowski does not teach their reagents provided together in the form of a kit composition, in light of the teachings of Zuk et al. regarding the advantages of providing reagents combined in a kit, it would have been prima facie obvious to combine together the necessary reagents (i.e. the CITE-seq antibodies and the reagents for single cell sequencing), in kit form.
Communication
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/STEFANIE J. KIRWIN/Examiner, Art Unit 1677
/ELLEN J MARCSISIN/Primary Examiner, Art Unit 1677
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