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 .
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 8/24/2023 and 7/15/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Specification
The disclosure is objected to because of the following informalities: paras. 13 and 14 of the instant specification refer to drawings, but no drawings have been provided. Given that Applicant does not refer to any particular figure numbers and drawings are only described generically, it is interpreted that Applicant did not intend to submit drawings. Applicant should thus remove language in the specification directed to drawings.
Appropriate correction is required.
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01. Specifically, hyperlinks appear in paras. 60 and 83.
Claim Interpretation
In claim 1, a “classification algorithm” is recited. Such an algorithm does not have a specific definition in the instant specification. In para. 58, statistical and classification methods for determining tumor types are recited, including calculating a probability that the tumor cells included in the biological sample are of at least one of a plurality of tumor types of which the primary site is specified. Paras. 88-89 show that classification models that predict tumor type can be used by classification algorithms. However, both of these sections simply recite examples for what can be used as or in a classification algorithm, and so are not considered limiting.
Thus, the term “classification algorithm” will be interpreted under its broadest reasonable interpretation, and will be considered to encompass any set of rules or operations designed to classify a primary site into a particular tumor type, with no particular limit on said types of rules or operations. This would include computer-learning algorithms, but also algorithms that can be completed manually by a user.
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.
Claim 1 is rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception without significantly more. The claim recite a natural law and abstract ideas.
Claim 1 is directed to a method for determining a primary tumor site via acquiring gene expression data in tumor cells of a sample and comparing it to specific gene expression data with a classification algorithm. The natural law recited is the correlation between the gene expression data and the primary site classification. The abstract ideas are the acquiring and classifying steps. “Acquiring” is not specifically defined by the instant specification, and so can involve simply looking at expression data that has already been obtained, without actually measuring said gene expression data in the claimed method. Thus, this step amounts to a mental process. For the classifying step, this can also involve only mental processes by comparing values for gene expression in the sample to those of the “specific gene expression data” that is from the known tumor types. As noted above, a “classification algorithm” can be performed manually, and simply needs particular rules/operations, and so would encompass comparing expression values to one another and making a classification determination if particular values are found. The classification algorithm itself may also encompass mathematical calculations, which is in itself also an abstract idea. See MPEP 2106.04(a) and MPEP 2106.04(b). These judicial exceptions are not integrated into a practical application because there is no required active treatment step or other step that integrates the judicial exception into a practical application. See MPEP 2106.04(d)(2). Additionally, the claim does not include additional elements that are sufficient to amount to significantly more than the judicial exception because they do not amount to more than well-understood, routine, and conventional activity in view of Tothill et al. (Pathology, 2015; cited in Applicant’s IDS) as evidenced by Illumina (“Array-Based Gene Expression Analysis,” 2011).
Tothiill teaches identifying primary tumor types in cancers of unknown primary (Summary). Tumor samples were used from patients who had cancer metastases with no clear primary tumor (page 7, column 2, para. 4). RNA was extracted and then subjected to the HumanHT-12 v4 BeadChip array from Illumina, which, as evidenced by Illumina, provides whole-genome level coverage (Illumina page 2, “HumanHT-12 Expression BeadChip” and Tothill page 8, column 1, “RNA extraction” and “Microarray gene expression”). A classification process was then used that generated algorithmic predication scores to determine primary tumor type (page 8, column 1, “Bioinformatics”). The classification process involved the use of a reference dataset of gene expression profiles that originated from tumor samples of known origin. This gene expression data was also based on RNA extraction and whole-genome expression data (page 8, “Classifier training,” and see the tumor types used in Table 1).
Thus, claim 1 is directed to judicial exceptions without significantly more
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 1 is 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 utilizing whole genome/whole transcriptome gene expression data for the biological sample in the method of claim 1, does not reasonably provide enablement for the use of any type of gene expression data that may be associated with a biological sample in the method of claim 1. 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 and/or use the invention commensurate in scope with these claims.
Factors to be considered in determining whether a disclosure meets the enablement requirement of 35 USC 112, first paragraph, have been described by the court in In re Wands, 8 USPQ2d 1400 (CA FC 1988). These factors include (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. Each of these factors is discussed below.
Nature of the Invention
Claim 1 is drawn to a method for determining a primary tumor site through the acquisition of gene expression data for a sample, and further using the gene expression data as a point of comparison with specific gene expression data and a classification algorithm.
The claimed method is classified in the unpredictable arts of molecular biology and biochemistry.
Breadth of the Claims
Claim 1 is broad in scope because it encompasses any type of gene expression data for the biological sample. This may be gene expression data for a few genes not associated with any cancer, genes associated with specific types of cancer a subject may not have, and whole genome/whole transcriptome gene expression data, for example.
Level of Skill in the Art
The ordinary artisan typically holds at least a master’s degree has several years of experience.
State of the Prior Art & Unpredictability
Concerning the claimed invention, what was (and is) unpredictable in the art is whether a particular type of “gene expression data” as claimed can perform as intended in the claimed method (i.e. being used to determine a primary tumor type). In methods similar to those claimed, particular gene expression datasets are mainly used, and so outside of these, it is not possible to know a priori that a particular type of “gene expression data” can performed as claimed.
For example, in the prior art, whole genome expression is often used on tumor samples of unknown primary origin to aid in determining the primary tumor type. Tothiill et al. (Pathology, 2015; cited in Applicant’s IDS) teaches identifying primary tumor types in cancers of unknown primary (Summary). Tumor samples were used from patients who had cancer metastases with no clear primary tumor (page 7, column 2, para. 4). RNA was extracted and then subjected to the HumanHT-12 v4 BeadChip array from Illumina, which, as evidenced by Illumina (“Array-Based Gene Expression Analysis,” 2011), provides whole-genome level coverage (Illumina page 2, “HumanHT-12 Expression BeadChip” and Tothill page 8, column 1, “RNA extraction” and “Microarray gene expression”). A classification process was then used that generated algorithmic predication scores to determine primary tumor type (page 8, column 1, “Bioinformatics”). The classification process involved the use of a reference dataset of gene expression profiles that originated from tumor samples of known of origin. This gene expression data was also based on RNA extraction and whole-genome expression data (page 8, “Classifier training,” and see the tumor types used in Table 1).
Additionally, the prior art utilizes specific genes that are known to be associated with cancers in particular tissues. Ayoubi et al. (US 2011/0230357 A1) classifies cancers of unknown primary (CUP; Abstract) by first obtaining sets of tissue-specific genes for different tissue types (Examples 1-2, paras. 98-105), and then utilizes those specific genes to classify unknown samples (Example 6, paras. 115-117)
In a further example, prior art may also encompass both methods. Abraham et al. (US 2022/0093217 A1) teaches molecular profiling to predict primary tumor lineage (Abstract). The reference teaches obtaining a biological sample from a subject, assessing biomarkers in the sample, and comparing the resulting biosignature to pre-determined biosignatures to determine primary tumor origin (para. 25). When assessing biomarkers, both specific biomarkers and whole exon/transcriptome sequencing may be used (para. 27 and see Tables 3-8).
Thus, the types of gene expression data typically gathered in the prior art either encompasses full genome/transcriptome data that can later be more narrowly compared with a reference dataset, or is a focused set of genes known to be associated with a particular type of cancer.
Guidance in the Specification and Examples
Regarding the use of “gene expression data” in the instant invention, it is first noted that the term does not have a specific definition. Para. 19 discusses “informative-genes” but does not limit the claimed invention to only using said “informative-genes” in “gene expression data.” Para. 23 states that “any appropriate system or method may be used for determining expression levels of informative-genes,” which would include methods that also measure levels of genes that are not informative.
In the working examples of the invention, Example 1 notes the use of multiple databases from which expression data was obtained (paras. 60-76), though these apply to tumors whose primary tumor type is already known. Examples 2-4 show further model configuration and algorithm information. These examples do not appear to discuss obtaining gene expression data for biological samples to classify their primary tumor type.
It is noted that Applicant has not provided any drawings concerning their invention.
In view of the unpredictability in the art discussed above, it is not clear that the results discussed by Applicant would extend over the full scope of the claimed invention.
Quantity of Experimentation
The ordinary artisan would have to conduct a very large quantity of highly unpredictable experimentation before being able to successfully practice the full scope of the claimed methods. Specifically, the ordinary artisan would have to determine, for each iteration of gene expression data encompassed by the claims, that a comparison could be made using existing primary tumor gene expression data and a classification algorithm to classify a tumor type in a sample. Based on the teachings in the art, which typically use whole genome/transcriptome methods or methods that target specifically chosen genes, this would be an inventive and unpredictable undertaking, requiring extensive experimentation in which there is no guarantee of success. The large quantity of experimentation and its unpredictability constitute undue experimentation.
Conclusion
In view of the foregoing, it is clear that the specification fails to enable the full scope of the claimed methods, and claim 1 is rejected under 35 U.S.C. 112(a) for failing to comply with the enablement requirement.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim 1 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Tothill et al. (Pathology, 2015; cited in Applicant’s IDS) as evidenced by Illumina (“Array-Based Gene Expression Analysis,” 20111).
Tothiill teaches identifying primary tumor types in cancers of unknown primary (Summary). Tumor samples were used from patients who had cancer metastases with no clear primary tumor (page 7, column 2, para. 4). RNA was extracted and then subjected to the HumanHT-12 v4 BeadChip array from Illumina, which, as evidenced by Illumina, provides whole-genome level coverage (Illumina page 2, “HumanHT-12 Expression BeadChip” and Tothill page 8, column 1, “RNA extraction” and “Microarray gene expression”). A classification process was then used that generated algorithmic predication scores to determine primary tumor type (page 8, column 1, “Bioinformatics”). The classification process involved the use of a reference dataset of gene expression profiles that originated from tumor samples of known of origin. This gene expression data was also based on RNA extraction and whole-genome expression data (page 8, “Classifier training,” and see the tumor types used in Table 1). Table 7 shows that the use of the classifier increased diagnostic accuracy.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claim 1 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 of copending Application No. 18/278,887 (reference application).
Although the claims at issue are not identical, they are not patentably distinct from each other because claim 1 of the ‘887 application encompasses a specific embodiment of instant claim 1. The claim concerns identifying a cancer of an unknown primary site by obtaining gene expression data from a tissue sample in which cancer metastasis has occurred. In order to use the method to effectively classify a primary site, the ordinary artisan would recognize that this sample would need to contain at least some cancer/tumor cells. Then, the method involves classifying the primary site of the cancer in the sample by comparing the gene expression data with pre-learned gene expression data (where the pre-learned data contains data for multiple cancer types). As the claim specifies rules and operations for the method by with the sample primary site is specified (i.e. classified), this would be considered a classification algorithm.
Thus, claim 1 of the ‘887 application reads on instant claim 1.
Claim 2 of the ‘887 application specifically states that cancer tissue should be sampled in the method of claim 1, and so also reads on instant claim 1.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
Claim 1 not currently allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to FRANCESCA F GIAMMONA whose telephone number is (571)270-0595. The examiner can normally be reached M-Th, 7-5pm.
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/FRANCESCA FILIPPA GIAMMONA/Examiner, Art Unit 1681
1 The date for this reference is obtained from the copyright information present at the bottom of the final page of the reference in the attached copy.