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 .
Election/Restrictions
Applicant’s election without traverse of group II, Detection of homogeneous intra-cellular labeling of CENP-A in terms of the number of CENP-A foci - Detection of homogeneous intra-tissue labeling of CENP-A in terms of the number of CENP-A foci in the reply filed on 4/7/2026 is acknowledged.
Claims 1-17 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 4/7/2026.
Priority
The instant application was filed 10/05/2023 and is a national stage entry of PCT/EP2022/059165 with an international filing date: 04/06/2022 and claims foreign priority to EP21305439.8, filed 04/06/2021.
Information Disclosure Statement
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.
The information disclosure statement (IDS) submitted on 10/5/2023 is being considered by the examiner.
Specification
The following guidelines illustrate the preferred layout for the specification of a utility application. These guidelines are suggested for the applicant’s use.
Arrangement of the Specification
As provided in 37 CFR 1.77(b), the specification of a utility application should include the following sections in order. Each of the lettered items should appear in upper case, without underlining or bold type, as a section heading. If no text follows the section heading, the phrase “Not Applicable” should follow the section heading:
(a) TITLE OF THE INVENTION.
(b) CROSS-REFERENCE TO RELATED APPLICATIONS.
(c) STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT.
(d) THE NAMES OF THE PARTIES TO A JOINT RESEARCH AGREEMENT.
(e) INCORPORATION-BY-REFERENCE OF MATERIAL SUBMITTED ON A READ-ONLY OPTICAL DISC, AS A TEXT FILE OR AN XML FILE VIA THE PATENT ELECTRONIC SYSTEM.
(f) STATEMENT REGARDING PRIOR DISCLOSURES BY THE INVENTOR OR A JOINT INVENTOR.
(g) BACKGROUND OF THE INVENTION.
(1) Field of the Invention.
(2) Description of Related Art including information disclosed under 37 CFR 1.97 and 1.98.
(h) BRIEF SUMMARY OF THE INVENTION.
(i) BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING(S).
(j) DETAILED DESCRIPTION OF THE INVENTION.
(k) CLAIM OR CLAIMS (commencing on a separate sheet).
(l) ABSTRACT OF THE DISCLOSURE (commencing on a separate sheet).
(m) SEQUENCE LISTING. (See MPEP § 2422.03 and 37 CFR 1.821 - 1.825). A “Sequence Listing” is required on paper if the application discloses a nucleotide or amino acid sequence as defined in 37 CFR 1.821(a) and if the required “Sequence Listing” is not submitted as an electronic document either on read-only optical disc or as a text file via the patent electronic system.
Thus the specification of 10/5/2023 should be amended to provide the incorporation by reference of the sequence listing.
Claim Objections
Claims 18-20 are objected to because of the following informalities:
Claim 18 recites, “a step of choosing one or more treatment options depending on the CENP-A pattern that is observed in the the tissue sample from the cancer of the subject.” The recitation of “the” twice appears to be a typographical error.
Appropriate correction is required.
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 18-20 rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
As set forth in In re Alonso 88 USPQ2d 1849 (Fed. Cir. 2008), at 1851:
The written description requirement of 35 U.S.C. § 112, ¶ 1, is straightforward: “The specification shall contain a written description of the invention ….” To satisfy this requirement, the specification must describe the invention in sufficient detail so “that one skilled in the art can clearly conclude that the inventor invented the claimed invention as of the filing date sought.” Lockwood v. Am. Airlines, Inc., 107 F.3d 1565, 1572 [41 USPQ2d 1961] (Fed. Cir. 1997); see also LizardTech, Inc. v. Earth Res. Mapping, Inc., 424 F.3d 1336, 1345 [76 USPQ2d 1724] (Fed. Cir. 2005); Eiselstein v. Frank, 52 F.3d 1035, 1039 [34 USPQ2d 1467] (Fed. Cir. 1995).
Alonso at 1852:
A genus can be described by disclosing: (1) a representative number of species in that genus; or (2) its “relevant identifying characteristics,” such as “complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics.” Enzo, 323 F.3d at 964.
In applying the test as set forth in Alonso, it is noted that applicant is claiming a method of treating a subject suffering from a cancer wherein one or more treatment options are chosen depending on a CENP-A pattern that is observed in a tissue sample from a cancer of the subject, comprising:- a step of labelling the tissue sample for CENP-A protein or for a homolog thereof; - a step of determining a nuclear pattern of CENP-A labelling in cells from the tissue sample, the step comprising determining a presence and a subnuclear distribution of CENP-A foci in the nucleus of the labelled cells from the tissue sample; - a step of choosing one or more treatment options depending on the CENP-A pattern that is observed in the the tissue sample from the cancer of the subject; and - a step of treating the subject with the one or more treatment options
Thus the claims broadly encompass any CENP-A protein or homolog from any species which have been labeled by any means. Further the claims encompass any means of labeling, any means of determining a nuclear patter for CENP-A, choosing any treatment options based on any CENP-A pattern. Further the claims encompass any cancer.
The specification teaches, The term "subject" is meant to refer to any mammal, e.g., mouse, rat, monkey, dog, human. In a preferred embodiment the subject is a human subject. “ However, Burgin (Journal of Mammalogy, 99(1):1–14, 2018) teaches, “We found 6,495 species of currently recognized mammals.” Thus the specification specifically envisions a genus of species encompassed by the specification. However the examples of the specification appear to be limited to human cancer. Thus while claiming a genus the specification appears to be limited to a single species.
Further the claims encompass any cancer. This is an enormous genus as each mammalian species have their own cancer. Further human cancers encompass an enormous genus encompassing brain cancer, bone cancer, breast cancer, etc. The teachings of the specification appear to be limited to HSNCC and breast cancer. Thus while the claims encompass a genus the specification appears to be 2 species.
Further the claims encompass any means of labeling and detecting CENP-A however the examples of the specification appear to be limited to immunohistochemistry. Thus while the claims encompass a genus the specification appears to be limited to a single species.
Further the claims encompass anything which can be considered a CENP-A protein or homolog thereof. While the specification states, “A "CENP-A protein or homolog thereof" is a protein whose sequence shares at least 80% homology with the CENP-A protein of SEQ ID NO:1 or of SEQ ID NO:2.” Thus the specification envision a genus of anything which can be considered have 80% homology to SEQ ID NO 1 or SEQ ID NO 2. However the examples are limited to the detection of human CENP-A. Thus the specification is limited to a species encompassed by the claims.
As detailed above the claims encompass numerous genus. However the specification does not provide a representative number of species or specific structure function relationship to provide adequate written description for the genus claimed.
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 18-20 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 18 recites, “a step of choosing one or more treatment options depending on the CENP-A pattern that is observed in the the tissue sample from the cancer of the subject.” The recitation appears to be vague unclear and incomplete as the claim provides no specific guidance on how the treatment options are determined. Thus the metes and bounds re unclear.
Claim 19 recites, “at least a part thereof being not distributed at the nuclear periphery of the nucleus or at the nucleolar periphery of the nucleus.” The specification states, “Nuclear periphery" when related to intranuclear CENP-A foci, refers to the localization of said foci just below nuclear envelope and tagging the shape of the nuclear envelope.” Thus the recitation is unclear as just below nuclear envelope is relative, confusing and unclear. Further it is unclear what “at least part of thereof “ encompasses, requires or excludes. Claim 19 recites, “detecting a homogeneous intra-cell CENP-A labelling in terms of size, number, and/or labelling intensity of CENP-A foci, and - detecting a homogeneous intra-tissue CENP-A labelling in terms of size, number, and/or labelling intensity of CENP-A foci” The specification states, “"Homogenous" when related to the CENP-A nuclear pattern of a tissue sample, refers to similarity of said pattern all through the tissue sample.” Thus homogenous is a relative term and the metes and bounds are unclear as the claims encompass a tissue sample that is all cancerous.
Further claim 19 recites, “the subject is diagnosed as suffering from a cancer responsive to chemotherapy and/or radiotherapy and/or concurrent chemoradiation therapy.” The recitation of responsive suggest there is non-responsive. The specification and claims provide no definition or standard to differentiate responsive from non-responsive. Thus the metes and bounds are unclear.
Claim 20 recites, “detecting intranuclear CENP-A foci, at least a part thereof being not distributed at the nuclear periphery of the nucleus or at the nucleolar periphery of the nucleus, and - detecting an intra-cell or an inter-cell heterogeneity in size, shape, or number of CENP- A foci.” The specification states, “Nuclear periphery" when related to intranuclear CENP-A foci, refers to the localization of said foci just below nuclear envelope and tagging the shape of the nuclear envelope.” Thus the recitation is unclear as just below nuclear envelope is relative, confusing and unclear. Further it is unclear what “at least part of thereof “ encompasses, requires or excludes.
Claim 20 recites, “the subject is diagnosed as suffering from a cancer likely resistant to chemotherapy and/or radiotherapy and/or concurrent chemoradiation therapy.” The recitation of resistant suggests there is responsive or non-resistant. The specification and claims provide a standard or definition to differentiate resistant from responsive or non-resistant. Thus the metes and bounds are unclear.
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 18-20 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural correlation and mental step without significantly more. The claim(s) recite(s) the abstract idea or mental steps of determining a nuclear pattern and choosing one or more treatment options. The claim is drawn to the mental step and or abstract idea/natural correlation of choosing treatment option based on the naturally occurring CENPA expression pattern. This judicial exception is not integrated into a practical application because the treatment step is generic and merely applying the judicial exception and encompasses watchful waiting. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claims do not require any specific reagents.
Claim analysis
The instant claim 18 is directed towards a method of treating a human patient with bortezomib comprising: a) measuring the amount of nucleic acid corresponding to a marker or plurality of markers in a human patient sample comprising myeloma tumor cells; b) comparing the amount of nucleic acid corresponding to the marker or plurality of markers to a control amount to select a patient whose amount of nucleic acid corresponding to the marker or plurality of markers indicates that the patient is expected to have a favorable outcome upon treatment with bortezomib, wherein a favorable outcome is expected if the nucleic acid is deleted or underexpressed; and c) treating the patient selected in b) with bortezomib, wherein the marker or plurality of markers is a marker gene or a plurality of marker genes selected from the group consisting of phosphatidylinositol glycan anchor biosynthesis, class K (PIGK), brix domain containing 5 (RPF1), and guanine nucleotide binding protein (G protein), gamma 5 (GNG5).. The correlation in the wherein clause in a natural correlation or phenomena. The comparing step is a mental step or abstract idea.
The step of labelling the tissue sample for CENP-A protein or for a homolog thereof is considered to be an active step requiring the analysis of a sample.
The step of determining a nuclear pattern of CENP-A labelling in cells from the tissue sample, the step comprising determining a presence and a subnuclear distribution of CENP-A foci in the nucleus of the labelled cells from the tissue sample; - a step of choosing one or more treatment options depending on the CENP-A pattern that is observed in the the tissue sample from the cancer of the subject; are mental step.
The step of treating the subject with the one or more treatment options is a generic step of merely applying the judicial exception with no particularly and /or encompasses watchful waiting.
Dependent claims set forth further limitations to with respect to nuclear patterns and treatments. The limitations with respect to patterns, resistance, responsive are vague and unclear as detailed above and thus are not considered substantially more or integrating the judicial exception.
According to the 2019 Patent Eligibility Guidance an initial two step analysis is required for determining statutory eligibility.
Step 1. Is the claim directed to a process, machine, manufacture, or composition of matter? In the instant case the Step 1 requirement is satisfied as the claims are directed towards a process.
Step 2A Prong one. Does the claim recite a law of nature, a natural phenomenon or an abstract idea? Yes, abstract idea/mental step and law of nature or natural phenomena.
With regards to claim 18, the claim recites, “step of determining a nuclear pattern of CENP-A labelling in cells from the tissue sample, the step comprising determining a presence and a subnuclear distribution of CENP-A foci in the nucleus of the labelled cells from the tissue sample; - a step of choosing one or more treatment options depending on the CENP-A pattern that is observed in the the tissue sample from the cancer of the subject.”
Further the choosing step is a natural correlation or phenomenon as it encompasses selecting treatment based on a naturally occurring expression pattern of CENPA.
The treating step is considered a generic step of merely applying the judicial exception with no specificity and/or encompasses watchful waiting.
Step 2A prong two. Does the claim recite additional elements that integrate the judicial exception into a practical application? The answer is no as treating step is considered a generic step of merely applying the judicial exception with no specificity and/or encompasses watchful waiting.
Step 2B. Does the claim recite additional elements that are significantly more than the judicial exceptions? No the claim requires no specific reagents or steps.
The specification teaches:
Any means that allows the specific detection and labelling of CENP-A protein or of a homolog thereof in a tissue sample is suitable for implementing methods of the invention and to be used in the kits according to the invention. Preferably, said means should allow to distinguish CENP-A clusterization in normal, non-cancerous, tissues or cells as evidenced and described herein. This can be easily tested by performing, e.g., IHC chromogenic staining or confocal microscopy fluorescence experiments. In a preferred embodiment, CENP-A pattern is detected by means of an antibody, a fragment thereof or an aptamer.
In a preferred embodiment, the methods of the invention, in any of the above embodiments, is implemented by using antibody(ies) specific to CENP-A in immunohistochemical (IHC) staining of tissue sample, which is a currently used method in the field of diagnosis and reviewed, for example by Ramos-Vara and Miller (2014) and detailed in the experimental section.
Further Lacoste (Molecular Cell 53, 631–644, February 20, 2014) demonstrates labeling and detection of CENPA is routine and conventional.
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.
Claim(s) 18-20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Lacoste (Molecular Cell 53, 631–644, February 20, 2014).
This rejection is set forth in part due to the 112 issues et forth above.
Lacoste teaches, “Centromeres are essential for ensuring proper chromosome segregation in eukaryotes. Their definition relies on the presence of a centromere-specific H3 histone variant CenH3, known as CENP-A in mammals. Its overexpression in aggressive cancers raises questions concerning its effect on chromatin dynamics and contribution to tumorigenesis. We find that CenH3 overexpression in human cells leads to ectopic enrichment at sites of active histone turnover involving a heterotypic tetramer containing CenH3 H4 with H3.3-H4. Ectopic localization of this particle depends on the H3.3 chaperone DAXX rather than the dedicated CenH3 chaperone HJURP. This aberrant nucleosome occludes CTCF binding and has a minor effect on gene expression. Cells overexpressing CenH3 are more tolerant of DNA damage. Both the survival advantage and CTCF occlusion in these cells are dependent on DAXX. Our findings illustrate how changes in histone variant levels can disrupt chromatin dynamics and suggests a possible mechanism for cell resistance to anticancer treatments.” (abs)
Lacoste teaches labeling and detection of CENP-A in cells (figure 1, figure 5)
Lacoste teaches, “ Notably, we find that ectopic CenH3 provides a significant survival advantage in the presence of DNA-damaging agents CPT and ionizing radiation. Both are used as anticancer treatments, raising the possibility that CenH3 misregulation could be an important factor determining increased resistance to cancer treatment or recurrence. “ (page 641, bottom 1st column, top of 2nd column)
While Lacoste teaches labeling of CENP-A protein or homologs thereof in cells, determining pattern of CENPA in cells, and ectopic expression of CENPA in cells is indicative of resistance to DNA damaging agents, Lacoste does not specifically teach choosing treatment based on nuclear distribution.
However it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claims to treat subject with ectopic nuclear expression of CENPA in cancer cells to identify if the cancer is likely to respond or resistant to DNA damaging agents and treating based on this identifying. The artisan would be motivated as Lacoste teaches, “ Notably, we find that ectopic CenH3 provides a significant survival advantage in the presence of DNA-damaging agents CPT and ionizing radiation. Both are used as anticancer treatments, raising the possibility that CenH3 misregulation could be an important factor determining increased resistance to cancer treatment or recurrence. “ The artisan would have a reasonable expectation of success as the artisan is merely using the teachings disclosed by Lacoste.
With regards to claims 19-20, as Lacoste teaches, “ Notably, we find that ectopic CenH3 provides a significant survival advantage in the presence of DNA-damaging agents CPT and ionizing radiation. Both are used as anticancer treatments, raising the possibility that CenH3 misregulation could be an important factor determining increased resistance to cancer treatment or recurrence. “
Thus it would have been prima facie obvious to one of skill in the art prior to the effective date of the claims to identify and treat cancers with normal expression patterns of CENPA in the nucleus with chemotherapy, radiation therapy, or chemoradiation therapy. It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claims to identify and treat subjects with ectopic or abnormal CENPA nuclear expression in cancer tissue as likely being resistant to hemotherapy, radiation therapy, or chemoradiation therapy. The artisan would have a reasonable expectation of success as Lacoste specifically teaches ectopic expression of CENPA is indicative of a survival advantage for DNA damaging agents and ionizing radiation.
Summary
No claims are allowed.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to STEVEN C POHNERT PhD whose telephone number is (571)272-3803. The examiner can normally be reached Monday- Friday about 6:00 AM-5:00 PM, every second Friday off.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Anne Gussow can be reached at (571)272-6047. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/Steven Pohnert/ Primary Examiner, Art Unit 1683
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