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 in the reply filed July 29, 2026 of species (a) outcome (ii); (b) the combination of Type I and Type II and high-grade serous ovarian carcinoma; (c) the combination of miR-187-5p, miR-6870-5p, and miR-1908-5p; and (d) 0.148 x (level of miR-187-5p) + 0.273 x (level of miR-6870-5p) + 0.186 x (level of miR-1908-5p) is acknowledged.
Claim(s) 61-80 is/are currently pending.
Claim(s) 62 is/are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected subject matter, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on July 29, 2026.
Claims 61 and 63-80 have been examined to the extent that they read the elected outcome, types of cancer, miRNAs, and formula. The additionally recited species have been withdrawn from consideration as being directed to non-elected subject matter.
Priority
It is acknowledged that the instant application is a continuation of international PCT Application No. PCT/JP2022/037272, filed October 5, 2022, and that it claims benefit of provisional 63/357,964, filed July 1, 2022, and provisional 63/318,105, filed March 9, 2022.
The provisional application 63/318,105 filed March 9, 2022 provided only a copy of non-patent literature attributed in part to the inventors of the instant application. This non-patent literature does not support all embodiments of the claims, including: indices other than prognostic indices generated using multivariate Cox regression models; miRNA other than miR-187-5p, miR-6870-5p, miR-1908-5p, miR-6727-5p, and miR-6750-5p); outcomes other than OS or PFS; cancers other than high-grade serous ovarian cancer; formulas other than those explicitly recited (pg. 4979, col. 1); cell-free samples other than serum; subjects treated with surgical operations or radiotherapy. Thus, the priority date is determined to be July 1, 2022 (the filing date of provisional application 63/357,964).
Specification
The disclosure is objected to because of the following informalities:
Par. 153 states that the p-value for high vs low values for the OS index is 0.036 and that the data is shown in Figure 4B. However, Figure 4B lists the p-value as 0.36. It is unclear which value is correct, and whether the comparison is actually statistically significant.
In par. 174, the groups of six and four miRNAs appear to have been improperly set forth; “Of six miRNAs” is followed by a list of four miRNAs and “Of four miRNAs” is followed by a list of seven miRNAs. It is not clear which miRNA were actually included in these subsets.
Appropriate correction is required.
Drawings
The drawings are objected to because the p-value indicated in Fig. 4B does not match the stated value in the specification (par. 153). Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
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 61 and 63-80 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 determining an outcome of an ovarian cancer based on indices derived from some combinations of miRNA in some subjects having ovarian cancer as elaborated below, does not reasonably provide enablement for determining an outcome of any ovarian cancer based on any indices derived from any other combinations of miRNA.
The embodiments that are enabled are:
Indices derived using means of statistical modeling/algorithms (such as those set forth in par. 119 and Examples 1-4)
Determination of survival outcomes in ovarian cancers according to the following combinations:
high-grade serous ovarian carcinoma
OS: using (miR-187-5p, miR-6870-5p, and miR-1908-5p)
PFS: using (miR-187-5p, miR-6870-5p, miR-6727-5p, miR-1908-5p, and miR-6850-5p) OR (miR-187-5p, miR-6870-5p, miR-6727-5p)
ovarian clear cell carcinoma
OS and PFS: using (miR-150-3p, miR-3195, and miR-7704)
The embodiments that are not enabled are:
Non-human subjects
ANY other types of indices derived in ANY possible way (e.g. appending identifiers; counting unique species; etc.)
ANY other possible combination of ANY miRNA to determine outcomes for ANY ovarian cancer
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
Claims 61 and 63-80 are drawn to a method of determining an outcome of ovarian cancer using an index derived from a plurality of miRNAs.
The claims recite a first step of obtaining an index derived from at least two miRNAs of a subject having ovarian cancer. In view of the recitation of “obtaining an index,” the claims encompass ANY manner of obtaining said index and ANY index (e.g. any composite value derived from a plurality of miRNA). In view of the recitation of “miRNAs,” the claims broadly encompass ANY plurality of miRNAs. Claim 67 limits the miRNA to particular species. In view of the recitation of “a subject,” the claims broadly encompass both human and non-human subjects. In view of the recitation of “ovarian cancer,” the claims broadly encompass ALL histological subtypes of ovarian cancer. Claim 66 limits the ovarian cancer to high-grade and low-grade serous ovarian carcinoma, endometrioid carcinoma, ovarian clear cell carcinoma, mucinous carcinoma, epithelial ovarian carcinoma, germ cell tumor, stromal cell tumor, or a combination thereof.
The claims recite a second step of determining a survival outcome of the ovarian cancer in the subject using the index, wherein the miRNA is obtained from a cell-free sample
The nature of the invention requires reliable correlations between ANY composite value (‘index’) of ANY combination of two or more miRNA and the prognosis of any ovarian cancer.
Teachings in the Specification and Examples
The specification describes that 210 miRNAs were selected for use based on their expression in exosomes derived from ovarian cancer cell lines (par. 143). All indices appear to have been generated using the output of multivariate Cox regression models for the candidate miRNA expression levels (par. 168)
The association between these miRNA and overall survival (OS) or progression-free survival (PFS) was assessed in serum from N=175 human subjects having high-grade serous ovarian cancer (HGSOC; par. 146). An index for overall survival was calculated using miR-187-5p and miR-6870-5p (par. 152 – index-OS1), but was not significantly different between high and low groups when assessed using Kaplan-Meier curves and multivariate Cox regression analysis. A second index for overall survival was calculated using miR-187-5p, miR-6870-5p, and miR-1908-5p. Index-OS2 was generated according to the following formula (par. 152):
0.148 x (level of miR-187-5p) + 0.273 x (level of miR-6870-5p) + 0.186 x (level of miR-1908-5p).
In this case, patients having a high index showed significantly shorter OS than those with low index. Indices for PFS were also found to be significantly associated with survival, and were generated according to the following formulas (par. 156):
Index-PFS1: 0.034 x (miR-187-5p) + 0.236 x (miR-6870-5p) + 0.504 x (miR-6727-5p) + 0.048 x (miR-1908-5p) + 0.251 x (miR-6850-5p)
Index-PFS2: 0.031 x (miR-187-5p) + 0.231 x (miR-6870-5p) + 0.351 x (miR-6727-5p)
The association between the 210 miRNA and overall survival was also assessed in N=66 subjects with ovarian clear cell carcinoma and FFPE/fresh-frozen samples (par. 165, 169). Overall survival was defined as the time from treatment initiation to death from any case (par. 168). Indices for overall survival were calculated using levels of miR-150-3p, miR-3195, and miR-7704 according to the formulas (par. 174):
Index-OS: 0.463 × (miR-150-3p) + 1.323 × (miR-3195) + 0.636 × (miR-7704).
Index-PFS: 0.399 × (miR-150-3p) + 1.426 × (miR-3195) + 0.480 × (miR-7704).
Kaplan-Meier curves and Pearson correlation coefficients showed that those with a low index had a significantly shorter OS than those with a high index (Fig. 12A; Table 9).
State of the Art and the Unpredictability of the Art
While methods of measuring miRNA levels and obtaining an index are known in the art, methods of correlating indices with phenotypes such as ovarian cancer prognosis are highly unpredictable. The unpredictability will be discussed below.
The claims broadly encompass ANY manner of obtaining an index derived from multiple miRNAs. Claims 68 and 69 require processing levels of miRNAs to generate the index, and claim 69 requires that the levels come from at least 2 subjects. Claim 70 requires processing of miRNA levels using an algorithm, claim 71 requires a linear regression model, and claim 72 requires that the linear regression model be a Cox model. However, the specification demonstrates only analysis of miRNA indices generated using multivariate Cox regression (par. 168). The term ‘index’ broadly encompasses any composite value – it would be highly unpredictable if any composite value derived from miRNAs would be informative regarding the outcome of ovarian cancer. For example, an index may be generated by appending the identifiers of miRNA present in a sample, or could be as simple as counting the number of unique species present in a sample. Given the same set of miRNAs, it is highly unpredictable whether indices derived in any given manner would be equally capable of determining an outcome of ovarian cancer in a subject. The specification provides support for only Cox regression and similar methodology.
The claims broadly encompass indices derived from ANY plurality of ANY miRNA. Claim 67 limits the miRNAs to a particular subset of 21 miRNAs. It is noted that there are thousands of miRNAs, and at least 858 miRNAs which may be cell-free and associated with ovarian cancer (Yokoi et al. Integrated extracellular microRNA profiling for ovarian cancer screening. Nat Commun. 2018 Oct 17;9(1):4319; provided as NPL #14 in IDS filed August 12, 2024). The instant specification teaches that, of a set of N=210 possible miRNA ovarian cancer prognostic biomarkers, very few are associated with survival outcomes when analyzed alone (par. 148, 171). The instant specification teaches indices derived from only a handful of combinations of that miRNA, and the indices not all informative. For example, of the five indices explicitly discussed in the specification, one (‘index-OS1’), derived from the levels of miR-187-5p and miR-6870-5p, was not significantly associated with survival (par. 152). This supports the finding that it is highly unpredictable as to whether any given index derived from any combination of ANY two or more miRNAs would be associated with ovarian cancer prognosis. The specification provides support only for an association between an ovarian cancer outcome and indices derived from the following four distinct combinations of miRNA:
high-grade serous ovarian carcinoma
Index-OS2: using miR-187-5p, miR-6870-5p, and miR-1908-5p
Index-PFS1: using miR-187-5p, miR-6870-5p, miR-6727-5p, miR-1908-5p, and miR-6850-5p
Index-PFS2: using miR-187-5p, miR-6870-5p, and miR-6727-5p
ovarian clear cell carcinoma
Index-OS and Index-PFS: using miR-150-3p, miR-3195, and miR-7704
The claims broadly encompass prognosis of ALL histological subtypes of ovarian cancer. Claim 66 limits the ovarian cancer to high-grade and low-grade serous ovarian carcinoma, endometrioid carcinoma, ovarian clear cell carcinoma, mucinous carcinoma, epithelial ovarian carcinoma, germ cell tumor, stromal cell tumor, or a combination thereof. The data in the specification regarding the relationship between miRNA and ovarian cancer is based only on high-grade serous ovarian carcinoma and ovarian clear cell carcinoma of various stages (Type I/Type II status in Experiments 1-4 does not appear to be disclosed). The prior art teaches that there is a large amount of unpredictability with regard to the relationship between miRNA levels and various histological subtypes. For example, Iorio (Iorio et al. MicroRNA signatures in human ovarian cancer. Cancer Res. 2007 Sep 15;67(18):8699-707) teaches that the specific miRNA which are up- or down-regulated in an ovarian cancer sample vs normal tissue differs according to subtype (Figure 3). This supports the finding that there is no predictable means for determining whether differential expression which indicates ovarian cancer prognosis in one subtype will also be predictive in a representative number of other subtypes. The data from specification only provides support for high-grade serous ovarian carcinoma (using miR-187-5p, miR-6870-5p, and miR-1908-5p) and ovarian clear cell carcinoma (miR-150-3p, miR-3195, and miR-7704), with no discussion of type.
The claims broadly encompass both human and non-human subjects. However, the data in the specification regarding the relationship between miRNA and ovarian cancer is based only on samples from human subjects. The prior art teaches that there is a large amount of unpredictability with regard to comparing miRNA expression in humans and nonhuman animals. For example, Alam (Alam et al. Comparative transcriptomics of primary cells in vertebrates. Genome Res. 2020 Jul;30(7):951-961) teaches that tissue-specific expression of a substantial proportion of miRNA differs significantly between humans and nonhuman animals, including mice, rats, dogs, and chickens (pg. 954, col. 2, 2nd par; Fig. 6). This supports the finding that there is no predictable means for determining whether differential expression which indicates ovarian cancer prognosis in humans will also be predictive in a representative number of non-human subjects. The specification only provides support for human subjects.
Quantity of Experimentation:
The quantity of experimentation necessary is great, on the order of many man-years, and then with little if any reasonable expectation of successfully enabling the full scope of the claims. In support of this position, it is noted that the claimed methods encompass being able to use ANY type of index derived from ANY plurality of ANY miRNA to determine an outcome of ANY type of ovarian cancer in a human or nonhuman subject.
In order to practice the breadth of the claimed invention one of skill in the art would first have to gather samples from human and non-human subjects having a representative number of ovarian cancer types. A representative number of kinds of indices would have to be derived from a representative number of combinations of two or more known miRNAs, and the survival outcomes measured. Then, sophisticated data analysis would have to be conducted to determine which indices would be predictive of ovarian cancer survival outcome. The specification has merely provided an invitation for further experimentation. 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. Attention is directed to Wyeth v. Abbott Laboratories 107 USPQ2d 1273, 1275, 1276 (Fed. Cir. June 2013):
Claims are not enabled when, at the effective filing date of the patent, one of ordinary skill in the art could not practice their full scope without undue experimentation. MagSil Corp. v. Hitachi Global Storage Techs., Inc., 687 F.3d 1377, 1380-81 [103 USPQ2d 1769] (Fed. Cir. 2012).
The remaining question is whether having to synthesize and screen each of at least tens of thousands of candidate compounds constitutes undue experimentation. We hold that it does. Undue experimentation is a matter of degree. Chiron Corp. v. Genentech, Inc., 363 F.3d 1247, 1253 [70 USPQ2d 1321] (Fed. Cir. 2004) (internal quotation omitted). Even "a considerable amount of experimentation is permissible," as long as it is "merely routine" or the specification "provides a reasonable amount of guidance" regarding the direction of experimentation. Johns Hopkins Univ. v. CellPro, Inc., 152 F.3d 1342, 1360- 61 [47 USPQ2d 1705] (Fed. Cir. 1998) (internal quotation omitted). Yet, routine experimentation is "not without bounds." Cephalon, Inc. v. Watson Pharm., Inc., 707 F.3d 1330, 1339 [105 USPQ2d 1817] (Fed. Cir. 2013). (Emphasis added)
In Cephalon, although we ultimately reversed a finding of nonenablement, we noted that the defendant had not established that required experimentation "would be excessive, e.g., that it would involve testing for an unreasonable length of time." 707 F .3d at 1339 (citing White Consol. Indus., Inc. v. Vega Servo-Control, Inc., 713 F.2d 788, 791 [218 USPQ 961] (Fed. Cir. 1983)). Finally, in In re Vaeck, we affirmed the PTO's nonenablement rejection of claims reciting heterologous gene expression in as many as 150 genera of cyanobacteria. 947 F.2d 488, 495-96 [20 USPQ2d 1438] (Fed. Cir. 1991). The specification disclosed only nine genera, despite cyanobacteria being a "diverse and relatively poorly understood group of microorganisms," with unpredictable heterologous gene expression. Id. at 496. (Emphasis added)
Additionally, attention is directed to Cephalon at 1823, citing White Consol. Indus., Inc. v. Vega Servo-Control, Inc., 218 USPQ 961, that work that would require 18 months to 2 years so to enable the full scope of an invention, even if routine, would constitute undue experimentation. As stated therein:
Permissible experimentation is, nevertheless, not without bounds. This court has held that experimentation was unreasonable, for example, where it was found that eighteen months to two years' work was required to practice the patented invention. See, e.g., White Consol. Indus., Inc. v. Vega Servo-Control, Inc., 713 F.2d 788, 791 [218 USPQ 961] Fed. Cir.1983). (Emphasis added)
Attention is also directed to MPEP 2164.06(b) and In re Vaeck, 20 USPQ2d 1438, 1445 (Fed. Cir. 1991).
Where, as here, a claimed genus represents a diverse and relatively poorly understood group of microorganisms, the required level of disclosure will be greater than, for example, the disclosure of an invention involving a "predictable" factor such as a mechanical or electrical element. See Fisher, 427 F.2d at 839, 166 USPQ at 24.
In view of such legal precedence, the aspect of having to work for so many years just to provide the starting materials for minute fraction of the scope of the claimed invention is deemed to constitute both an unreasonable length of time and undue experimentation.
Conclusions:
Herein, although the level of 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 skill in the art to make and use the invention as broadly 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 61 and 63-80 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.
Claims 61 and 63-80 are rejected because claim 80 recites that the treatment comprises surgical operation, chemotherapy, or radiotherapy. This recitation is confusing because claim 61 recites that treatment may occur (and be used for measuring ovarian cancer outcomes), but does not require it. Therefore, it is unclear whether treatment is truly optional in claim 61 and whether it remains optional in claim 80. As a result, one of skill in the art would not be able to determine the metes and bounds of the claimed subject matter.
Claim 65 is rejected for the recitation of “a combination thereof” because it is unclear what is meant by ‘a combination of Type I and Type II ovarian cancer.’ Ovarian cancer Type I and Type II tumors are divided into two broad categories based on progression and molecular changes, but the distinction between Type I and Type II is not well defined for some histological subtypes (Cho et al. Ovarian Cancer. Annual Review of Pathology: Mechanisms of Disease 4:287-313: pg. 303, col. 2, 1st par.). It is unclear if the limitation ‘a combination thereof’ is intended to encompass cancers where the Type is not defined/definable (such as ovarian clear cell carcinoma), or if it’s intended to encompass ovarian cancers having tumors of both Type I and Type II, or something else. As a result, one of skill in the art would not be able to determine the metes and bounds of the claimed subject matter.
Claims 68-73 are rejected for the recitation of “said derivatives thereof” in claims 68-70 and 73 as lacking antecedent basis. Claim 61, on which they depend, does not recite “miRNAs or derivatives thereof,” and therefore it is unclear which derivatives are being referred to. As a result, one of skill in the art would not be able to determine the metes and bounds of the claimed subject matter.
Claims 68-73 are rejected for the recitation of “derivatives thereof” as indefinite. The specification and claims do not provide a limiting definition for the term “derivative,” and it unclear what the limitation requires. The plain meaning of the term “derivative” in this context encompasses nucleic acids which are formed from a miRNA of interest (i.e. alternative products of a pre-miRNA). However, the miRNAs of the instant application are disclosed as mature products with no explicit contemplation of their alternatives (i.e. only miR-187-5p is recited and not pre-miR-187 and/or miR-187-3p), which is inconsistent with the plain meaning. Therefore, it is unclear whether the limitation is intended to encompass alternative products of the same pre-miRNA (e.g. miR-187-3p and miR-187-5p), homologous miRNA, mutant miRNA, or something else. As a result, one of skill in the art would not be able to determine the metes and bounds of the claimed subject matter.
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 74 and 77 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.
Claim 74 is rejected because it requires that the cell-free sample recited in claim 61 comprises a bodily fluid. It is not clear how a cell-free sample obtained from a subject could be any sample other than a bodily fluid. Therefore, claim 74 does not appear to further limit the subject matter of claim 61.
Claim 77 is rejected because it requires that the miRNAs recited in claim 61 are cell-free miRNA. It is not clear how ‘cell-free miRNAs’ differ from miRNAs which are obtained from a cell-free sample, as is already required by claim 61. Therefore, claim 77 does not appear to further limit the subject matter of claim 61.
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 § 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 61 and 63-80 are rejected under 35 U.S.C. 101 because the claimed invention is directed to judicial exception without significantly more. The claims have been evaluated using the 2019 Revised Patent Subject Matter Eligibility Guidance (see Federal Register Vol. 84, No. 4, Monday, January 7, 2019).
Step 1: The claims are directed to the statutory category of a process.
Step 2A, prong one: Evaluate Whether the Claim Recites a Judicial Exception
The instant claims recite a law of nature. The claims recite a correlation between the expression levels of a plurality of miRNAs (in the form of an index) and outcomes of ovarian cancer in a subject. This type of correlation is a consequence of natural processes, similar to the naturally occurring correlation found to be a law of nature by the Supreme Court in Mayo.
The instant claims recite abstract ideas. The claims recite a step of “determining” an outcome. Neither the specification nor the claims set forth a limiting definition for “determining” and the claims do not set forth how this step is accomplished. The “determining” step broadly encompasses mental processes. For example, one may “determine” an outcome by looking at data and thinking about what a likely prognosis is. Mental processes, which are concepts performed in the human mind (including observation, evaluation, judgement, and opinions) are considered to be abstract ideas.
The claims recite a step of “obtaining an index.” Neither the claims nor the specification provide a limiting definition of the term ‘index,’ and the plain meaning of the term encompasses any composite value. The broadest reasonable interpretation of the “obtaining an index” step is that it may be accomplished by a mental process. For example, one may “obtain” the index by thinking about combining two values. Mental processes, which are concepts performed in the human mind (including observation, evaluation, judgement, and opinions) are considered to be abstract ideas. In addition, the process of ‘obtaining an index’ in the broadest sense would also involve the use of mathematical comparisons and operations, constituting a mathematical process. Claim 73 recites that the index comprises specific numerical formulas. Numerical formulas or equations are considered to be mathematical concepts.
The claims recite a step of “processing” levels of miRNA to generate an index. Neither the claims nor the specification set forth criteria for processing and the claims do not set forth how this step is accomplished. The broadest reasonable interpretation of the “processing” step is that it may be accomplished by a mental process. For example, one may “process” levels of miRNA by looking at the expression levels and thinking about how they may be combined to generate the index. Mental processes, which are concepts performed in the human mind (including observation, evaluation, judgement, and opinions) are considered to be abstract ideas. In addition, ‘processing levels to generate an index in the broadest sense would also involve the use of mathematical comparisons and operations, constituting a mathematical process.
Step 2A, prong two: Evaluate Whether the Judicial Exception Is Integrated Into a Practical Application
The claims do NOT recite additional steps or elements that integrate the recited judicial exception(s) into a practical application of the exception(s). For example, the claims do not practically apply the judicial exception by including one or more additional elements that the courts have stated integrate the exception into a practical application:
An additional element reflects an improvement in the functioning of a computer, or an improvement to other technology or a technological field;
An additional element that applies or used a judicial exception to affect a particular treatment or prophylaxis for a disease or medical condition;
An additional element implements a judicial exception with, or uses a judicial exception in conjunction with, a particular machine or manufacture that is integral to the claim;
An additional element effects a transformation or reduction of a particular article to a different state or thing;
An additional element applies or uses the judicial exception in some other meaningful way beyond generally linking the use of the judicial exception to a particular technological environment, such that the claim as a whole is more than a drafting effort designed to monopolize the exception.
In addition to the judicial exceptions, the claims recite limitations of the outcome (e.g. claims 61, 63, 64), the subject (e.g. claims 65, 66, 80), the miRNA (e.g. claims 67, 73), and the sample (e.g. claims 74-78). These elements fail to meaningfully limit the claims and are the equivalent of adding the words “apply it” to the judicial exceptions.
In addition to the judicial exceptions, the claims recite limitations of how the miRNA levels are processed and how the index is generated (claims 68-72). These limitations are not considered to integrate the judicial exceptions into a practical application because they merely add insignificant extra-solution activity to the judicial exceptions, or merely link the judicial exceptions to a particular field of use.
In addition to the judicial exceptions, claim 79 recites a step of “extracting” miRNA from a subject. This step is not considered to integrate the judicial exceptions into a practical application because it merely adds insignificant extra-solution activity (data gathering) to the judicial exceptions.
Step 2B: Evaluate Whether the Claim Provides and Inventive Concept
In addition to the judicial exceptions, the claims recite steps of “extracting” miRNA, limitations of the outcome, subject, miRNA, and sample, and limitations of how miRNA levels are processed and how the index is generated. These steps do not amount to significantly more because they simply append well-understood, routine, and conventional activities previously known in the art, specified at a high level of generality, to the judicial exceptions.
These steps are recited a high level of generality. Extracting miRNA and selecting subjects, samples, miRNA targets, and measured outcomes merely instruct a scientist to use any known technique for extracting miRNA and designing a study. Use of Cox regression models to derive coefficients to generate an index is conventional. The claims do not require the use of any particular non-conventional reagents or equipment or any particular methodology. When recited at this high level of generality, there is no meaningful limitation that distinguishes the claimed steps from well-understood, routine, and conventional activities engaged in by scientists prior to applicant’s invention and at the time the application was filed. Although the claims recite particular formulas comprised in an index, these formulas are themselves judicial exceptions and cannot provide an inventive concept.
Additionally, the teachings in the specification demonstrate the well-understood, routine, and conventional nature of additional elements because it teaches that the additional elements are well-known or commercially available. For example, the specification teaches the following:
PNG
media_image1.png
399
393
media_image1.png
Greyscale
PNG
media_image2.png
173
399
media_image2.png
Greyscale
PNG
media_image3.png
271
394
media_image3.png
Greyscale
Further, it is noted that the courts have recognized the following laboratory techniques as well-understood, routine, and conventional activity in the life science arts when they are claimed in a merely generic manner (e.g. at a high level of generality) or as insignificant extra-solution activity.
Determining the level of a biomarker in blood by any means, 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);
Using polymerase chain reaction to amplify and detect DNA, Genetic Techs. v. Merial LLC, 818 F.3d 1369, 1376, 118 USPQ2d 1541, 1546 (Fed. Cir. 2016); Ariosa Diagnostics, Inc. v. Sequenom, Inc., 788 F.3d 1371, 1377, 115 USPQ2d 1152, 1157 (Fed. Cir. 2015);
Detecting DNA or enzymes in a sample, Sequenom, 788 F.3d at 1377-78, 115 USPQ2d at 1157); Cleveland Clinic Foundation 859 F.3d at 1362, 123 USPQ2d at 1088 (Fed. Cir. 2017);
Immunizing a patient against a disease, Classen Immunotherapies, Inc. v. Biogen IDEC, 659 F.3d 1057, 1063, 100 USPQ2d 1492, 1497 (Fed. Cir. 2011);
Analyzing DNA to provide sequence information or detect allelic variants, Genetic Techs., 818 F.3d at 1377; 118 USPQ2d at 1546;
Freezing and thawing cells, Rapid Litig. Mgmt. 827 F.3d at 1051, 119 USPQ2d at 1375;
Amplifying and sequencing nucleic acid sequences, University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 764, 113 USPQ2d 1241, 1247 (Fed. Cir. 2014)
For the reasons set forth above the claims are not directed to patent eligible subject matter.
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 pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Claims 61, 63, 64, 66-72, and 74-80 are rejected under 35 U.S.C. 103 as unpatentable over Kida (published May 7, 2020; Patent Application Publication No. US 2020/0140956; English language version of FOR #4 WO 2018/199275 A1, publication of PCT/JP2018/017125, in IDS filed 8/12/24) in view of Johansen (WO 2012/155918 A2, published on Nov. 22, 2012; ).
This rejection under 35 U.S.C. 103 is directed to the embodiment of a method of determining an outcome of an ovarian cancer based on indices derived from combination of miR-187-5p, miR-6870-5p, and miR-1908-5p, which is an enabled embodiment indicated in the scope of enablement under 35 U.S.C. 112(a)
Regarding claim 61, Kida teaches a method, comprising: obtaining an index (par. 921) derived from at least two miRNAs of a subject having an ovarian cancer (par. 371); and determining a status of said ovarian cancer in said subject using said index. Kida teaches that said at least two miRNAs are obtained from a cell-free sample of said subject (par. 92).
Regarding claim 66, Kida teaches ovarian cancers comprising epithelial ovarian carcinoma and germ cell stromal tumors (par. 85-87).
Regarding claim 67, Kida teaches miRNAs comprising at least two of miR-187-5p, miR-6870-5p, miR-1908-5p, (par. 56), which is the elected species by Applicants of the instant application.
Regarding claims 68-70, Kida teaches processing the levels of a plurality of miRNAs from at least 2 subjects using an algorithm to generate an index (par. 921-922).
Regarding claims 74-76, Kida teaches cell-free bodily fluid samples comprising serum, urine, sweat, and plasma (par. 63, 92).
Regarding claims 77 and 78, Kida teaches miRNA derived from extracellular vesicles (par. 68-69, 71).
Regarding claim 79, Kida teaches extracting miRNA (par. 882-883).
Regarding claim 80, Kida teaches determining a status in subjects treated with chemotherapy (par. 888).
Regarding claims 61 and 63, Kida does not explicitly teach determining an outcome of the ovarian cancer comprising an amount of time that said subject is alive, subsequent to (1) when said subject is determined to have said ovarian cancer or (2) when said subject receives said treatment for said ovarian cancer.
Regarding claim 64, Kida does not teach that the outcome comprises progress-free survival, overall survival, or a combination thereof.
Regarding claim 80, Kida does not explicitly teach measuring outcomes comprising an amount of time a subject is alive subsequent to when the subject receives a treatment comprising surgical operations, chemotherapy, or radiotherapy.
Regarding claims 71 and 72, Kida does not teach indices generated using algorithms comprising linear regression models or Cox models. Kida does teach using other algorithms for generating indices (par. 922) and evaluating ovarian cancers (par. 933).
Regarding claims 61, 63, 64, and 80, Johansen teaches determining cancer outcomes comprising overall survival (pg. 21, 3rd full par. ), which is defined as an amount of time that a subject is alive subsequent to when the subject has received a treatment for cancer, wherein the treatment is surgery (pg. 5: Definitions).
Regarding claims 71 and 72, Johansen teaches generating an index using an algorithm comprising a linear regression model in the form of a Cox model. For clarity, the expression levels of multiple miRNAs were measured and then analyzed using multivariate Cox models. Each miRNA’s expression was multiplied by its coefficient (obtained from Cox regression) and then all relevant terms were summed to generate the prognostic index (pg. 6, ln 1-17; pg. 53, ln. 18-22).
It would have been obvious to a person with ordinary skill in the art before the effective filing date of the instant invention to combine the teachings of Kida and Johansen. One would have been motivated to do so in order to improve and specify follow-up treatment and management in patients diagnosed with cancer (pg. 2, 2nd to last par.) using appropriate methods of data analysis. One would have had reasonable expectation of success because both Kida and Johansen are concerned with cancer assessment based on miRNA expression, and at least one miRNA (miR-187) is shared between the diagnostic method of Kida (par. 54) and the prognostic method of Johansen (pg. 3, last par.).
Claims 65 is rejected under 35 U.S.C. 103 as unpatentable over Kida (published May 7, 2020; Patent Application Publication No. US 2020/0140956; English language version of FOR #4 in IDS filed 8/12/24) in view of Johansen (published Nov. 22, 2012; International Publication No. WO 2012/155918), as applied to claim 61 above, and further in view of Cho (published online Oct. 8, 2008; Cho et al. Annual Review of Pathology: Mechanisms of Disease 4:287-313).
Kida and Johansen teach the limitations of claim 61, as discussed above.
Regarding claim 65, Kida and Johansen do not teach methods of determining outcomes in Type I/Type II ovarian cancer.
Cho teaches ovarian cancers defined as Type I and Type II (Table I).
It would have been obvious to a person with ordinary skill in the art before the effective filing date of the instant invention to combine the teachings of Kida and Johansen with the teachings of Cho. One would have been motivated to do so in order to address the heterogeneity of ovarian cancers, ultimately improving detection and treatment (pg. 304, col. 1). One would have had reasonable expectation of success because Cho, Kida, and Johansen are all concerned with molecular and clinical analysis of subjects with various cancers, and because Cho explains that Type I/II classification encompasses groups of histopathological classifications such as serous/mucinous/endometrioid carcinoma (pg. 303, col. 1).
Claim 73 is rejected under 35 U.S.C. 103 as unpatentable over Kida (published May 7, 2020; Patent Application Publication No. US 2020/0140956; English language version of FOR #4 in IDS filed 8/12/24) in view of Johansen (published Nov. 22, 2012; International Publication No. WO 2012/155918), as applied to claims 61 and 68 above, and further in view of Royston (published May 30, 2006; Royston et al. Br J Cancer. 2006 Jun 19;94(12):1785-8).
Kida and Johansen teach the limitations of claims 61 and 68, as discussed above.
Regarding claim 73, Kida and Johansen teach formulas which are generic to the claimed formula of: 0.148 x (level of miR-187-5p) + 0.273 x (level of miR-6870-5p) + 0.186 x (level of miR-1908-5p). Note that this formula can be described as the sum of the levels of three miRNA multiplied by their corresponding coefficients.
Kida teaches linear discriminant analysis according to the general formula (par. 923):
PNG
media_image4.png
115
247
media_image4.png
Greyscale
Here, the value of an explanatory variable x (such as miRNA expression level) is multiplied by a coefficient w, and the results are summed for all terms.
Johansen teaches prognostic indices generated according to the following formula (pg. 53, ln. 20):
PNG
media_image5.png
39
162
media_image5.png
Greyscale
Here, miRNA expression levels x are multiplied by their corresponding Cox regression coefficient β and then summed for all terms.
Regarding claim 73, Kida and Johansen do not explicitly teach that the index comprises a formula comprising the levels of a plurality of miRNAs wherein the formula comprises: 0.148 x (level of miR-187-5p) + 0.273 x (level of miR-6870-5p) + 0.186 x (level of miR-1908-5p). That is, they do not explicitly teach the coefficients recited in the claims.
Royston teaches prognostic indices generated using weights (coefficients) taken from fitted Cox models (pg. 1786, col. 2, par. 3-8). Royston teaches that the coefficients “are determined by fitting Cox model to the data in the usual way” – in other words, Royston teaches that the coefficients of a prognostic index (such as that taught by Johansen) are results-effective variables for achieving the best fit of a model or the best index for prognostic prediction. Therefore, absent evidence of criticality, it would have been obvious to a person with ordinary skill in the art before the effective filing date of the instant invention to optimize the indices taught by Kida and Johansen to arrive at the claimed formula. One would have had reasonable expectation of success because Royston teaches various means of generating the relevant indices (pg. 1786, col. 2, par. 7).
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 61 and 63-80 are provisionally rejected on the grounds of nonstatutory double patenting as being unpatentable over claims 19-73, 77-81, 88, and 95-125 of co-pending Application No. 17/641,054, in view of in view of Johansen (published Nov. 22, 2012; International Publication No. WO 2012/155918).
Although the claims at issue are not identical, they are not patentably distinct from one another. Both sets of claims are drawn to methods (19-21, 33, 55). Both sets of claims require:
Obtaining an index derived from at least two miRNAs of a subject having ovarian cancer (claim 19-21, 33, 55). In this case, the index is the composite expression levels of a plurality of miRNA.
Determining an outcome of ovarian cancer in a subject using the index, wherein at least two miRNAs are obtained from a cell-free sample (claim 19).
The reference does not explicitly teach that the outcome comprises an amount of time that the subject is alive, subsequent to (1) when the subject is determined to have ovarian cancer, or (2) when the subject receives treatment for ovarian cancer. However, it would be obvious to try using the miRNA for such prognosis, in order to improve and specify follow-up treatment and management in patients diagnosed with cancer (Johansen: pg. 2, 2nd to last par.). This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 61 and 63-80 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of Patent No. 10,975,444, in view of Johansen (published Nov. 22, 2012; International Publication No. WO 2012/155918).
Although the claims at issue are not identical, they are not patentably distinct from one another. Both sets of claims are drawn to methods. Both sets of claims require:
Obtaining an index derived from at least two miRNAs of a subject having ovarian cancer (claim 1, 3). In this case, the index is the composite expression levels of a plurality of miRNA (claim 3, 9-12, 15-18)
Determining an outcome of ovarian cancer in a subject using the index, wherein at least two miRNAs are obtained from a cell-free sample (claim 6).
The reference does not explicitly teach that the outcome comprises an amount of time that the subject is alive, subsequent to (1) when the subject is determined to have ovarian cancer, or (2) when the subject receives treatment for ovarian cancer. However, it would be obvious to try using the miRNA for such prognosis, in order to improve and specify follow-up treatment and management in patients diagnosed with cancer (Johansen: pg. 2, 2nd to last par.).
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Christine M Jones whose telephone number is (571)272-2585. The examiner can normally be reached Monday - Friday, 8AM - 4PM.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Wu-Cheng Winston Shen can be reached at (571)272-3157. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/C.M.J./Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682
Prosecution Insights